Contingent cardio-protection for epilepsy patients

ABSTRACT

Disclosed are methods and systems for treating epilepsy by stimulating a main trunk of a vagus nerve, or a left vagus nerve, when the patient has had no seizure or a seizure that is not characterized by cardiac changes such as an increase in heart rate, and stimulating a cardiac branch of a vagus nerve, or a right vagus nerve, when the patient has had a seizure characterized by cardiac changes such as a heart rate increase.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority to co-pendingU.S. patent application Ser. No. 16/911,592 entitled “ContingentCardio-Protection for Epilepsy Patients”, filed on Jun. 25, 2020, whichclaims priority to and is a continuation-in-part of U.S. patentapplication Ser. No. 13/288,886 entitled “Classifying Seizures AsEpileptic or Non-Epileptic Using Extra-Cerebral Body Data”, filed onNov. 3, 2011, which claims priority to and is a continuation-in-part ofU.S. patent application Ser. No. 13/098,262 entitled “Detecting,Quantifying, and/or Classifying Seizures Using Multimodal Data”, filedon Apr. 29, 2011 (now U.S. Pat. No. 8,382,667), which claims priority toand is a continuation-in-part of U.S. patent application Ser. No.12/896,525 entitled “Detecting, Quantifying, and/or Classifying SeizuresUsing Multimodal Data”, filed on Oct. 1, 2010 (now U.S. Pat. No.8,337,404) and U.S. patent application Ser. No. 16/911,592 is acontinuation-in-part of and claims priority to co-pending U.S. patentapplication Ser. No. 16/679,216 entitled “Contingent Cardio-ProtectionFor Epilepsy Patients”, filed on Nov. 10, 2019, which is acontinuation-in-part of and claims priority to co-pending U.S. patentapplication Ser. No. 15/437,155 entitled “Contingent Cardio-ProtectionFor Epilepsy Patients”, filed on Feb. 20, 2017 (now U.S. Pat. No.10,682,515), which claims priority to and is a divisional application ofU.S. patent application Ser. No. 14/050,173 entitled “ContingentCardio-Protection For Epilepsy Patients”, filed on Oct. 9, 2013 (nowU.S. Pat. No. 9,579,506), which claims priority to and is acontinuation-in-part of U.S. patent application Ser. No. 13/601,099entitled “Contingent Cardio-Protection For Epilepsy Patients”, filed onAug. 31, 2012 (now U.S. Pat. No. 9,314,633), which claims priority toand is a continuation-in-part of U.S. patent application Ser. No.12/020,195 entitled “Method, Apparatus and System for Bipolar ChargeUtilization during Stimulation by an Implantable Medical Device”, filedon Jan. 25, 2008 (now U.S. Pat. No. 8,260,426) and claims priority toand is a continuation-in-part of U.S. patent application Ser. No.12/020,097 entitled “Changeable Electrode Polarity Stimulation by anImplantable Medical Device”, filed on Jan. 25, 2008 (now U.S. Pat. No.8,565,867) all of which are incorporated herein by reference in theirentireties.

BACKGROUND OF THE DISCLOSURE

This disclosure relates generally to medical devices, and, moreparticularly, to methods, apparatus, and systems for performing vagusnerve stimulation (VNS) for treating epileptic seizures characterized bycardiac changes, including ictal tachycardia. This disclose also relatesto medical device systems and methods capable of classifying anoccurring or impending seizure as epileptic or non-epileptic usingextra-cerebral body data.

DESCRIPTION OF THE RELATED ART

While seizures are the best known and most studied manifestation ofepilepsy, cardiac alterations are prevalent and may account for the highrate of sudden unexpected death (SUDEP) in these patients. Thesealterations may include changes in rate (most commonly tachycardia,rarely bradycardia or asystole), rhythm (PACs, PVCs), conduction (e.g.,bundle branch block) and repolarization abnormalities (e.g., Q-Tprolongation, which occurs primarily during (ictal) but also betweenseizures (inter-ictally). In addition, S-T segment depression (a sign ofmyocardial ischemia) is observed during epileptic seizures. Significantelevations in heart-type fatty acid binding protein (H-FABP), acytoplasmic low-molecular weight protein released into the circulationduring myocardial injury have been documented in patients with epilepsyand without evidence of coronary artery disease, not only duringseizures but also during free-seizure periods. H-FABP is a moresensitive and specific marker of myocardial ischemia than troponin I orCK-MB. Elevations in H-FABP appear to be un-correlated with duration ofillness, of the recorded seizures, or with the Chalfont severity scoreof the patients.

The cardiac alterations in epilepsy patients, both during and betweenseizures, have a multi-factorial etiology, but a vago-sympatheticimbalance seems to play a prominent role in their generation. Themajority of epileptic seizures enhance the sympathetic tone (plasmanoradrenaline and adrenaline rise markedly after seizure onset) causingtachycardia, arterial hypertension and increases in the respiratoryrate, among others. Recurrent and frequent exposure to the outpouring ofcatecholamines associated with seizures in patients withpharmaco-resistant epilepsies may, for example, account forabnormalities that increase the risk of sudden death such asprolongation of the Q-T interval which leads to often fataltachyarrhythmias such as torsade de pointe. Further evidence in supportof the role of catecholamines in SUDEP is found in autopsies of SUDEPvictims, revealing interstitial myocardial fibrosis (a risk factor forlethal arrhythmias), myocyte vacuolization, atrophy of cardiomyocytes,leukocytic infiltration, and perivascular fibrosis. Restoration of thesympathetic-parasympathetic tone to normal levels, a therapeuticobjective that may be accomplished by enhancing parasympathetic activitythrough among others, electrical stimulation of the vagus nerve, maydecrease the rate and severity of cardiac and autonomic co-morbiditiesin these patients.

While there have been significant advances over the last several decadesin treatments for epileptic seizures, the management ofco-morbidities—in particular the cardiac alterations associated withseizures—remains largely unaddressed. There is a need for improvedepilepsy treatments that address cardiac impairments associated withseizures. Pharmacological therapies for neurological diseases (includingepilepsy) have been available for many decades. A more recent treatmentfor neurological disorders involves electrical stimulation of a targettissue to reduce symptoms or effects of the disorder. Such therapeuticelectrical signals have been successfully applied to brain, spinal cord,and cranial nerves tissues improve or ameliorate a variety ofconditions. A particular example of such a therapy involves applying anelectrical signal to the vagus nerve to reduce or eliminate epilepticseizures, as described in U.S. Pat. Nos. 4,702,254, 4,867,164, and5,025,807, which are hereby incorporated herein by reference in theirentirety.

The endogenous electrical activity (i.e., activity attributable to thenatural functioning of the patient's own body) of a neural structure maybe modulated in a variety of ways. One such way is by applying exogenous(i.e., from a source other than the patient's own body) electrical,chemical, or mechanical signals to the neural structure. In someembodiments, the exogenous signal (“neurostimulation” or“neuromodulation”) may involve the induction of afferent actionpotentials, efferent action potentials, or both, in the neuralstructure. In some embodiments, the exogenous (therapeutic) signal mayblock or interrupt the transmission of endogenous (natural) electricalactivity in the target neural structure. Electrical signal therapy maybe provided by implanting an electrical device underneath the skin of apatient and delivering an electrical signal to a nerve such as a cranialnerve.

In one embodiment, the electrical signal therapy may involve detecting asymptom or event associated with the patient's medical condition, andthe electrical signal may be delivered in response to the detection.This type of stimulation is generally referred to as “closed-loop,”“active,” “feedback,” “contingent” or “triggered” stimulation.Alternatively, the system may operate according to a predeterminedprogram to periodically apply a series of electrical pulses to the nerveintermittently throughout the day, or over another predetermined timeinterval. This type of stimulation is generally referred to as“open-loop,” “passive,” “non-feedback,” “non-contingent” or“prophylactic,” stimulation.

In other embodiments, both open- and closed-loop stimulation modes maybe used. For example, an open-loop electrical signal may operate as a“default” program that is repeated according to a programmed on-time andoff-time until a condition is detected by one or more body sensorsand/or algorithms. The open-loop electrical signal may then beinterrupted in response to the detection, and the closed-loop electricalsignal may be applied—either for a predetermined time or until thedetected condition has been effectively treated. The closed-loop signalmay then be interrupted, and the open-loop program may be resumed.Therapeutic electrical stimulation may be applied by an implantablemedical device (IMD) within the patient's body or, in some embodiments,externally.

Closed-loop stimulation of the vagus nerve has been proposed to treatepileptic seizures. Many patients with intractable, refractory seizuresexperience changes in heart rate and/or other autonomic body signalsnear the clinical onset of seizures. In some instances the changes mayoccur prior to the clinical onset, and in other cases the changes mayoccur at or after the clinical onset. Where the changes involves heartrate, most often the rate increases, although in some instances a dropor a biphasic change (up-then-down or down-then-up) may occur. It ispossible using a heart rate sensor to detect such changes and toinitiate therapeutic electrical stimulation (e.g., VNS) based on thedetected change. The closed-loop therapy may be a modified version of anopen-loop therapy. See, e.g., U.S. Pat. Nos. 5,928,272, and 6,341,236,each hereby incorporated by reference herein. The detected change mayalso be used to warn a patient or third party of an impending oroccurring seizure.

VNS therapy for epilepsy patients typically involves a train ofelectrical pulses applied to the nerve with an electrode pair includinga cathode and an anode located on a left or right main vagal trunk inthe neck (cervical) area. Only the cathode is capable of generatingaction potentials in nerve fibers within the vagus nerve; the anode mayblock some or all of the action potentials that reach it (whetherendogenous or exogenously generated by the cathode). VNS as an epilepsytherapy involves modulation of one or more brain structures. Therefore,to prevent the anode from blocking action potentials generated by thecathode from reaching the brain, the cathode is usually located proximalto the brain relative to the anode. For vagal stimulation in the neckarea, the cathode is thus usually the upper electrode and the anode isthe lower electrode. This arrangement is believed to result in partialblockage of action potentials distal to or below the anode (i.e., thosethat would travel through the vagus nerve branches innervating thelungs, heart and other viscerae). Using an upper-cathode/lower-anodearrangement has also been favored to minimize any effect of the vagusnerve stimulation on the heart.

Stimulation of the left vagus nerve, for treatment of epilepsy hascomplex effects on heart rate (see Frei & Osorio, Epilepsia 2001), oneof which includes slowing of the heart rate, while stimulation of theright vagus nerve has a more prominent bradycardic effect. Electricalstimulation of the right vagus nerve has been proposed for use in theoperating room to slow the heart during heart bypass surgery, to providea surgeon with a longer time period to place sutures between heartbeats(see, e.g., U.S. Pat. No. 5,651,373). Some patents discussing VNStherapy for epilepsy treatment express concern with the risk ofinadvertently slowing the heart during stimulation. In U.S. Pat. No.4,702,254, it is suggested that by locating the VNS stimulationelectrodes below the inferior cardiac nerve, “minimal slowing of theheart rate is achieved” (col. 7 lines 3-5), and in U.S. Pat. No.6,920,357, the use of a pacemaker to avoid inadvertent slowing of theheart is disclosed.

Cranial nerve stimulation has also been suggested for disorders outsidethe brain such as those affecting the gastrointestinal system, thepancreas (e.g., diabetes, which often features impaired production ofinsulin by the islets of Langerhans in the pancreas), or the kidneys.Electrical signal stimulation of either the brain alone or the organalone may have some efficacy in treating such medical conditions, butmay lack maximal efficacy.

While electrical stimulation has been used for many years to treat anumber of conditions, a need exists for improved VNS methods of treatingepilepsy and its cardiac co-morbidities as well as other brain andnon-brain disorders.

Non-epileptic generalized seizures, also known as pseudo-seizures,psychogenic seizures, or hysterical seizures, are often misdiagnosed asepileptic at large cost to the patient, caregivers, and the health caresystem. The diagnosis of non-epileptic seizures is difficult, asevidenced by the long mean latency (7 years) between the onset ofmanifestations and accurate diagnosis that the patient's seizures arenon-epileptic. Approximately 10-30% of patients referred to epilepsycenters because of suspected epileptic seizures are diagnosed as havingnon-epileptic seizures. While carrying the incorrect diagnosis ofepileptic seizures, patients are treated with anti-seizure medications.Since these lack efficacy (due to the fundamental pathophysiologicdifferences between epileptic and non-epileptic seizures), emergencyroom visits and hospitalizations are frequent. The observation that theprevalence of non-epileptic seizures is higher in patients with epilepsy(estimates put the number of patients having both epileptic andnon-epileptic seizures at 10-50% of all epileptic patients seen atspecialty centers) than in the general population, makes accuratedifferentiation between them even more challenging.

Video-EEG monitoring, the current “gold standard” for differentiation,requires hospitalization, usually for several days, at high expense tothe health care system and great inconvenience to the patient andhis/her loved ones.

SUMMARY OF THE DISCLOSURE

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising receiving at least one body datastream, analyzing the at least one body data stream using a seizure orevent detection algorithm to detect whether or not the patient is havingand/or has had an epileptic seizure, receiving a cardiac signal of thepatient, applying a first electrical signal to a vagus nerve of thepatient based on a determination that the patient is not having and/orhas not had an epileptic seizure characterized by a decrease in thepatient's heart rate, wherein the first electrical signal is not a vagusnerve conduction blocking electrical signal, and applying a secondelectrical signal to a vagus nerve of the patient based on adetermination that the patient is having and/or has had an epilepticseizure characterized by a decrease in the patient's heart rate, whereinthe second electrical signal is a pulsed electrical signal that blocksaction potential conduction in the vagus nerve.

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising sensing a cardiac signal and akinetic signal of the patient, analyzing at least one of the cardiacsignal and the kinetic signal; determining whether or not the patienthas had an epileptic seizure based on the analyzing; in response to adetermination that the patient has had an epileptic seizure, determiningwhether or not the seizure is characterized by a decrease in thepatient's heart rate, applying a first electrical signal to a vagusnerve of the patient based on a determination that the patient has hadan epileptic seizure characterized by a decrease in the patient's heartrate, wherein the first electrical signal is a pulsed electrical signalthat blocks action potential conduction in the vagus nerve; and applyinga second electrical signal to a vagus nerve of the patient based on oneof a) a determination that the patient has not had an epileptic seizure,and b) a determination that the patient has had an epileptic seizurethat is not characterized by a decrease in the patient's heart rate,wherein the second electrical signal is not a vagus nerve conductionblocking electrical signal.

In one aspect, the present disclosure relates to a system for treating amedical condition in a patient, comprising at least one electrodecoupled to a vagus nerve of the patient, a programmable electricalsignal generator, a sensor for sensing at least one body data stream, aseizure detection module capable of analyzing the at least one body datastream and determining, based on the analyzing, whether or not thepatient is having and/or has had an epileptic seizure, a heart ratedetermination unit capable of determining a heart rate of a patientproximate in time to an epileptic seizure detected by the seizuredetection module, and a logic unit for applying a first electricalsignal to the vagus nerve using the at least one electrode based on adetermination by the seizure detection module that the patient is havingand/or has had an epileptic seizure characterized by a decrease in thepatient's heart rate, wherein the first electrical signal is a pulsedelectrical signal that blocks action potential conduction in the vagusnerve, and for applying a second electrical signal to the vagus nerveusing the at least one electrode as a cathode based upon one of a) adetermination that the patient is not having and/or has not had anepileptic seizure, and b) a determination that the patient is havingand/or has had an epileptic seizure that is not characterized by adecrease in the patient's heart rate, wherein the second electricalsignal is not a vagus nerve conduction blocking electrical signal. Inone embodiment, the seizure detection module may comprise the heart ratedetermination unit.

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising applying a first electrical signal toa vagus nerve of the patient, wherein the first electrical signal is anopen-loop electrical signal having a programmed on-time and a programmedoff-time, sensing at least one body signal of the patient, determiningthe start of an epileptic seizure based on the at least one body signal,determining whether or not the seizure is characterized by a decrease inthe patient's heart rate, applying a second, closed-loop electricalsignal to a vagus nerve of the patient based on a determination that theepileptic seizure is not characterized by a decrease in the patient'sheart rate, and applying a third, closed-loop electrical signal to avagus nerve of the patient based on a determination that the seizure ischaracterized by a decrease in the patient's heart rate, wherein thethird electrical signal is applied to block action potential conductionon the vagus nerve.

In one aspect, the present disclosure relates to a method of controllinga heart rate of an epilepsy patient comprising sensing a kinetic signalof the patient; analyzing said kinetic signal to determine at least onekinetic index; receiving a cardiac signal of the patient; analyzing thecardiac signal to determine the patient's heart rate; determining if thepatient's heart rate is commensurate with the at least one kineticindex; and applying a first electrical signal to a vagus nerve of thepatient based on a determination that the patient's heart rate is notcommensurate with the kinetic index. In one embodiment, the at least onekinetic index comprises at least one of an activity level or an activitytype of the patient, and determining if the heart rate is commensuratewith the kinetic index comprises determining if the heart rate iscommensurate with the at least one of an activity level or an activitytype.

In one aspect, the present disclosure relates to a method of controllinga heart rate of an epilepsy patient comprising sensing at least one of akinetic signal and a metabolic (e.g., oxygen consumption) signal of thepatient; receiving a cardiac signal of the patient; analyzing thecardiac signal to determine the patient's heart rate; determining if thepatient's heart rate is commensurate with the at least one of a kineticand a metabolic signal of the patient; and applying a first electricalsignal to a vagus nerve of the patient based on a determination that thepatient's heart rate is not commensurate with the at least one of akinetic signal and a metabolic signal. In one embodiment, the methodfurther comprises determining at least one of an activity level or anactivity type of the patient based on the at least one of a kinetic anda metabolic signal, and determining if the heart rate is commensuratewith the kinetic signal comprises determining if the heart rate iscommensurate with the at least one of an activity level or an activitytype.

In one aspect, the present disclosure relates to a method of treating apatient having epilepsy comprising sensing at least one body signal ofthe patient; determining whether or not the patient is having or has hadan epileptic seizure based on the at least one body signal; sensing acardiac signal of the patient; determining whether or not the seizure isassociated with a change in the patient's cardiac signal; applying afirst therapy to a vagus nerve of the patient based on a determinationthat the patient is having or has had an epileptic seizure that is notassociated with a change in the patient's cardiac signal, wherein thefirst therapy is selected from an electrical, chemical, mechanical(e.g., pressure) or thermal signal. The method further comprisesapplying a second therapy to a vagus nerve of the patient based on adetermination that the patient has had an epileptic seizure associatedwith a change in the patient's cardiac signal, wherein the secondtherapy is selected from an electrical, chemical, mechanical (e.g.,pressure) or thermal signal. In some embodiments, a third therapy may beapplied to a vagus nerve based a determination that the patient has nothad an epileptic seizure, wherein the third therapy is selected form anelectrical, chemical, mechanical or thermal signal.

In one embodiment, the present disclosure provides a method ofdistinguishing a non-epileptic seizure from an epileptic seizure in apatient, comprising: detecting a seizure in a patient based on at leastone first body signal of the patient selected from an autonomic signal,a neurologic signal, a metabolic signal, an endocrine signal, and atissue stress marker signal; analyzing at least one second body signalof the patient selected from an autonomic signal, a neurologic signal, ametabolic signal, an endocrine signal, and a tissue stress markersignal; determining, based on the analyzing of the at least one secondbody signal, at least a first classification index comprising at leastone of an epileptic seizure index and a non-epileptic seizure index; andclassifying the seizure as one of a non-epileptic seizure or anepileptic seizure based on the at least a first classification index.

In one embodiment, the present disclosure provides a method ofdistinguishing an epileptic seizure from a non-epileptic seizure,comprising: identifying an unclassified seizure that is one of anepileptic seizure or a non-epileptic seizure; determining a firstseizure classification index having an index class selected from aneurologic index class, an autonomic index class, a motor index class, atissue stress marker index class, or a metabolic index class;determining a second seizure classification index having an index classselected from a neurologic index class, an autonomic index class, amotor index class, a tissue stress marker index class, or a metabolicindex class; classifying said seizure as one of an epileptic seizure ora non-epileptic seizure based on both said first and said second seizureclassification indices; and taking at least one further action based onsaid classifying, wherein said at least one further action is selectedfrom:

-   -   a notification that the seizure is non-epileptic; issuing a        notification that the seizure is epileptic; administering a        therapy for a non-epileptic seizure; administering a therapy for        an epileptic seizure; or logging at least one of whether the        seizure is an epileptic or non-epileptic seizure and at least        one of the date of the seizure, the time of occurrence of the        seizure, the severity of the seizure, the time elapsed from a        previous seizure, or the frequency per unit time of the same        type of seizure.

In one embodiment, the present disclosure provides a method, comprising:receiving a kinetic signal from at least one target of the patient'sbody; determining at least one kinetic index based on said kineticsignal; identifying an unclassified seizure based on the at least onekinetic index; receiving at least one of a non-kinetic neurologic indexand an autonomic index; and classifying the seizure as an epilepticseizure or non-epileptic seizure based on the at least one of anon-kinetic neurologic index and an autonomic index.

In one embodiment, the present disclosure provides a medical devicesystem, comprising: at least one sensor configured to receive at leastone of an autonomic signal indicative of an autonomic activity of apatient, a neurologic signal indicative of a neurologic activity of saidpatient, a metabolic signal indicative of a metabolic activity of saidpatient, an endocrine signal indicative of an endocrine activity of saidpatient, or a tissue stress marker signal indicative of a tissue stressmarker activity of said patient; a seizure detection unit configured todetect a seizure in a patient based on said at least one autonomic,neurologic, metabolic, endocrine, or tissue stress marker signal; atleast one classification index determination unit configured todetermine at least a first classification index selected from anautonomic index, a neurologic index, a metabolic index, an endocrineindex, and a tissue stress marker index; and a seizure classificationunit configured to classify said epileptic seizure as one of anepileptic seizure and a non-epileptic seizure based at least in part onsaid at least a first classification index.

In one embodiment, the present disclosure provides a non-transitive,computer-readable storage device for storing data that when executed bya processor, perform a method as described above.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure may be understood by reference to the followingdescription taken in conjunction with the accompanying drawings, inwhich like reference numerals identify like elements, and in which:

FIGS. 1A-1E provide stylized diagrams of an implantable medical deviceimplanted into a patient's body for providing first and secondelectrical signals to a vagus nerve of a patient for treating epilepticseizures, in accordance with one illustrative embodiment of the presentdisclosure;

FIG. 2 illustrates a block diagram depiction of an implantable medicaldevice of FIG. 1 , in accordance with one illustrative embodiment of thepresent disclosure;

FIG. 3 illustrates a block diagram depiction of an electrode polarityreversal unit shown in FIG. 2 , in accordance with one illustrativeembodiment of the present disclosure;

FIG. 4 illustrates a flowchart depiction of a method for providing firstand second electrical signals to a main trunk and a cardiac branch of avagus nerve, respectively, based upon whether or not the patient ishaving and/or has had an epileptic seizure, in accordance with anillustrative embodiment of the present disclosure;

FIG. 5 illustrates a flowchart depiction of a method for providing firstand second electrical signals to a main trunk and a cardiac branch of avagus nerve, respectively, based upon whether or not at least one of acardiac signal and a kinetic signal indicates that the patient is havingand/or has had an epileptic seizure, and whether the seizure ischaracterized by an increase in heart rate, in accordance with anillustrative embodiment of the present disclosure;

FIG. 6 illustrates a flowchart depiction of a method for providing afirst, open-loop electrical signal to a main trunk of a vagus nerve, asecond, closed-loop electrical signal to the main trunk of the vagusnerve based upon the patient having had an epileptic seizure notcharacterized by an increase in heart rate, and a third, closed-loopelectrical signal to a cardiac branch of a vagus nerve based upon thepatient having had an epileptic seizure characterized by an increase inheart rate, in accordance with an illustrative embodiment of the presentdisclosure; and

FIG. 7 is a flowchart depiction of a method for providing closed-loopvagus nerve stimulation for a patient with epilepsy by stimulating aright vagus nerve in response to detecting a seizure with tachycardiaand stimulating a left vagus nerve in the absence of such a detection.For example if a recumbent person's heart rate is 55 bpm and itincreases to 85 during a seizure, this is not clinical/pathologicaltachycardia, but may be considered tachycardia within the meaning ofsome embodiments of the present disclosure.

FIG. 8 is a flowchart depiction of a method for providing a closed-looptherapy to a vagus nerve of a patient with epilepsy in response todetecting a seizure associated with a heart rate decrease, wherein saidtherapy blocks impulse conduction along at least one vagus nerve.

FIG. 9 is a flowchart depicting a method for providing closed-loop vagusnerve stimulation based on an assessment of whether the patient's heartrate is commensurate with the patient's activity level or activity type.

FIG. 10 is a flowchart depicting a method for providing closed-loopvagus nerve stimulation based on a determination that the patient'sheart rate is incommensurate with the patient's activity level oractivity type, and further in view of whether the incommensurate changesinvolves relative tachycardia or relative bradycardia.

FIG. 11 is a graph of heart rate versus time, according to oneembodiment.

FIG. 12 is another graph of heart rate versus time, according to oneembodiment.

FIG. 13 is another graph of heart rate versus time, according to oneembodiment.

FIG. 14 is another graph of heart rate versus time, according to oneembodiment.

FIG. 15 is another graph of heart rate versus time, according to oneembodiment.

FIG. 16 is a flowchart of a therapy procedure, according to oneembodiment.

FIG. 17 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 18 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 19 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 20 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 21 is a graph relating to the automated detection and control ofictal and peri-ictal chronotropic instability, according to oneembodiment.

FIG. 22 provides a stylized diagram of a medical device for classifyinga seizure as epileptic or non-epileptic, in accordance with oneillustrative embodiment of the present disclosure.

FIG. 23 provides a block diagram of a medical device system thatincludes a medical device and a monitoring unit, in accordance with oneillustrative embodiment of the present disclosure.

FIG. 24A provides a block diagram of an autonomic signal module of amedical device, in accordance with one illustrative embodiment of thepresent disclosure.

FIG. 24B provides a block diagram of a neurologic signal module of amedical device, in accordance with one illustrative embodiment of thepresent disclosure.

FIG. 24C provides a block diagram of a metabolic signal module of amedical device, in accordance with one illustrative embodiment of thepresent disclosure.

FIG. 24D provides a block diagram of an endocrine signal module of amedical device, in accordance with one illustrative embodiment of thepresent disclosure.

FIG. 24E provides a block diagram of a stress marker signal module of amedical device, in accordance with one illustrative embodiment of thepresent disclosure.

FIG. 24F provides a block diagram of a classification unit of a medicaldevice, in accordance with one illustrative embodiment of the presentdisclosure.

FIG. 25 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure.

FIG. 26 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure.

FIG. 27 shows a flowchart depiction of a method, in accordance with oneillustrative embodiment of the present disclosure.

FIGS. 28A and 28B compare simulated, non-limiting (a) epileptic and (b)non-epileptic movements of an arm, as represented by the path traced byan accelerometer, as seen from in front of, to the side of, and above apatient.

While the disclosure is susceptible to various modifications andalternative forms, specific embodiments thereof have been shown by wayof example in the drawings and are herein described in detail. It shouldbe understood, however, that the description herein of specificembodiments is not intended to limit the disclosure to the particularforms disclosed, but on the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the disclosure as defined by the appended claims.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

Illustrative embodiments of the disclosure are described herein. Forclarity, not all features of an actual implementation are provided indetail. In any actual embodiment, numerous implementation-specificdecisions must be made to achieve the design-specific goals. Such adevelopment effort, while possibly complex and time-consuming, wouldnevertheless be a routine task for persons of skill in the art giventhis disclosure.

This application does not intend to distinguish between components thatdiffer in name but not function. “Including” and “includes” are used inan open-ended fashion, and should be interpreted to mean “including, butnot limited to.” “Couple” or “couples” are intended to mean either adirect or an indirect electrical connection. “Direct contact,” “directattachment,” or providing a “direct coupling” indicates that a surfaceof a first element contacts the surface of a second element with nosubstantial attenuating medium there between. Small quantities ofsubstances, such as bodily fluids, that do not substantially attenuateelectrical connections do not vitiate direct contact. “Or” is used inthe inclusive sense (i.e., “and/or”) unless a specific use to thecontrary is explicitly stated.

“Electrode” or “electrodes” may refer to one or more stimulationelectrodes (i.e., electrodes for applying an electrical signal generatedby an IMD to a tissue), sensing electrodes (i.e., electrodes for sensinga body signal), and/or electrodes capable of either stimulation orsensing. “Cathode” and “anode” have their standard meanings, as theelectrode at which current leaves the IMD system and the electrode atwhich current enters the IMD system, respectively. Reversing thepolarity of the electrodes can be effected by any switching techniqueknown in the art.

A “pulse” is used herein to refer to a single application of electricalcharge from the cathode to target neural tissue. A pulse may includeboth a therapeutic portion (in which most or all of the therapeutic oraction-potential-generating effect occurs) and a charge-balancingportion in which the polarity of the electrodes are reversed and theelectrical current is allowed to flow in the opposite direction to avoidelectrode and/or tissue damage. Individual pulses are separated by atime period in which no charge is delivered to the nerve, which can becalled the “interpulse interval.” A “burst” is used herein to refer to aplurality of pulses, which may be separated from other bursts by aninterburst interval in which no charge is delivered to the nerve. Theinterburst intervals have a duration exceeding the interpulse intervalduration. In one embodiment, the interburst interval is at least twiceas long as the interpulse interval. The time period between the end ofthe last pulse of a first burst and the initiation of the first pulse ofthe next subsequent burst can be called the “interburst interval.” Inone embodiment, the interburst interval is at least 100 msec.

A plurality of pulses can refer to any of (a) a number of consecutivepulses within a burst, (b) all the pulses of a burst, or (c) a number ofconsecutive pulses including the final pulse of a first burst and thefirst pulse of the next subsequent burst.

“Stimulate,” “stimulating” and “stimulator” may generally refer toapplying a signal, stimulus, or impulse to neural tissue (e.g., a volumeof neural tissue in the brain or a nerve) for affecting it neuronalactivity. While the effect of such stimulation on neuronal activity istermed “modulation,” for simplicity, the terms “stimulating” and“modulating”, and variants thereof, are sometimes used interchangeablyherein. The modulation effect of a stimulation signal on neural tissuemay be excitatory or inhibitory, and may potentiate acute and/orlong-term changes in neuronal activity. For example, the modulationeffect of a stimulation signal may comprise: (a) initiating actionpotentials in the target neural tissue; (b) inhibition of conduction ofaction potentials (whether endogenous or exogenously generated, orblocking their conduction (e.g., by hyperpolarizing or collisionblocking), (c) changes in neurotransmitter/neuromodulator release oruptake, and (d) changes in neuroplasticity or neurogenesis of braintissue. Applying an electrical signal to an autonomic nerve may comprisegenerating a response that includes an afferent action potential, anefferent action potential, an afferent hyperpolarization, an efferenthyperpolarization, an afferent sub-threshold depolarization, and/or anefferent sub-threshold depolarization. The terms tachycardia andbradycardia are used here in a relative (i.e., any decrease or decreasein heart rate relative to a reference value) or in an absolute sense(i.e., a pathological change relative to a normative value). Inparticular, “tachycardia is used interchangeably with an increase heartrate and “bradycardia” may be used interchangeably with a decrease inheart rate.

A variety of stimulation therapies may be provided in embodiments of thepresent disclosure. Different nerve fiber types (e.g., A, B, andC-fibers that may be targeted) respond differently to stimulation fromelectrical signals because they have different conduction velocities andstimulation threshold. Certain pulses of an electrical stimulationsignal, for example, may be below the stimulation threshold for aparticular fiber and, therefore, may generate no action potential. Thus,smaller or narrower pulses may be used to avoid stimulation of certainnerve fibers (such as C-fibers) and target other nerve fibers (such as Aand/or B fibers, which generally have lower stimulation thresholds andhigher conduction velocities than C-fibers). Additionally, techniquessuch as a pre-pulse may be employed wherein axons of the target neuralstructure may be partially depolarized (e.g., with a pre-pulse orinitial phase of a pulse) before a greater current is delivered to thetarget (e.g., with a second pulse or an initial phase such a stair steppre-pulse to deliver a larger quantum of charge). Furthermore, opposingpolarity phases separated by a zero current phase may be used to exciteparticular axons or postpone nerve fatigue during long term stimulation.

Cranial nerve stimulation, such as vagus nerve stimulation (VNS), hasbeen proposed to treat a number of medical conditions, includingepilepsy and other movement disorders, depression and otherneuropsychiatric disorders, dementia, traumatic brain injury, coma,migraine headache, obesity, eating disorders, sleep disorders, cardiacdisorders (such as congestive heart failure and atrial fibrillation),hypertension, endocrine disorders (such as diabetes and hypoglycemia),and pain, among others. See, e.g., U.S. Pat. Nos. 4,867,164; 5,299,569;5,269,303; 5,571,150; 5,215,086; 5,188,104; 5,263,480; 6,587,719;6,609,025; 5,335,657; 6,622,041; 5,916,239; 5,707,400; 5,231,988; and5,330,515. Despite the variety of disorders for which cranial nervestimulation has been proposed or suggested, the fact that detailedneural pathways for many (if not all) cranial nerves remain relativelyunknown, makes predictions of efficacy for any given disorder difficultor impossible. Even if such pathways were known, the precise stimulationparameters that would modulate particular pathways relevant to aparticular disorder generally cannot be predicted.

Cardiac signals suitable for use in embodiments of the presentdisclosure may comprise one or more of an electrical (e.g., EKG),acoustic (e.g., phonocardiogram or ultrasound/ECHO), force or pressure(e.g., apexcardiogram), arterial pulse pressure and waveform or thermalsignals that may be recorded and analyzed to extract features such asheart rate, heart rate variability, rhythm (regular, irregular, sinus,ventricular, ectopic, etc.), morphology, etc.

It appears that sympatho-vagal imbalance (lower vagal and highersympathetic tone) plays an important role in generation of a widespectrum of ictal and interictal alterations in cardiac dynamics,ranging from rare unifocal PVCs to cardiac death. Without being bound bytheory, restoration of the vagal tone to a level sufficient tocounteract the pathological effects of elevated catecholamines may servea cardio-protective purpose that would be particularly beneficial inpatients with pharmaco-resistant epilepsies, who are at highest risk forSUDEP.

In one embodiment, the present disclosure provides methods and apparatusto increase cardiac vagal tone in epilepsy patients by timely deliveringtherapeutic electrical currents to the trunks of the right or left vagusnerves or to their cardiac rami (branches), in response to increases insympathetic tone, by monitoring among others, heart rate, heart rhythm,EKG morphology, blood pressure, skin resistance, catecholamine or theirmetabolites and neurological signals such as EEG/ECoG, kinetic (e.g.,amplitude velocity, direction of movements) and cognitive (e.g., complexreaction time).

In one embodiment, the present disclosure provides a method of treatinga medical condition selected from the group consisting of epilepsy,neuropsychiatric disorders (including but not limited to depression),eating disorders/obesity, traumatic brain injury, addiction disorders,dementia, sleep disorders, pain, migraine, endocrine/pancreaticdisorders (including but not limited to diabetes), motility disorders,hypertension, congestive heart failure/cardiac capillary growth, hearingdisorders, angina, syncope, vocal cord disorders, thyroid disorders,pulmonary disorders, gastrointestinal disorders, kidney disorders, andreproductive endocrine disorders (including infertility).

FIGS. 1A-1E depict a stylized implantable medical system 100 forimplementing one or more embodiments of the present disclosure. FIGS. 1Aand 1B illustrate an electrical signal generator 110 having main body112 comprising a case or shell (commonly referred to as a “can”) 121)(FIG. 1B) with a header 116 for connecting to a lead assembly 122. Anelectrode assembly 125, preferably comprising at least an electrodepair, is conductively connected to the distal end of an insulated,electrically conductive lead assembly 122, which preferably comprises aplurality of lead wires (at least one wire for each electrode of theelectrode assembly 125). Lead assembly 122 is attached at its proximalend to one or more connectors on header 116 (FIG. 1B).

Electrode assembly 125 may be surgically coupled to a target tissue fordelivery of a therapeutic electrical signal, which may be a pulsedelectrical signal. The target tissue may be a cranial nerve, such as avagus nerve 127 (FIGS. 1A, 1C-E) or another cranial nerve such as atrigeminal nerve. Electrode assembly 125 includes one or more electrodes125-1, 125-2, 125-3, which may be coupled to the target tissue. Theelectrodes may be made from any of a variety of conductive metals knownin the art, e.g., platinum, iridium, oxides of platinum or iridium, orcombinations of the foregoing. In one embodiment, the target tissue is avagus nerve 127, which may include an upper main trunk portion 127-1above a cardiac branch 127-2, and a lower main trunk portion 127-3 belowthe cardiac branch.

In one embodiment, at least one electrode may be coupled to the maintrunk of the vagus nerve, and at least one electrode 125-2 may becoupled to a cardiac branch 127-2 of the vagus nerve (FIG. 1C). The atleast one main trunk electrode may be coupled to an upper main trunk127-1 (e.g., electrode 125-1, FIG. 1C) or a lower main trunk 127-3(e.g., electrode 125-3). The at least one main trunk electrode (125-1,125-3) may be used as a cathode to provide a first electrical signal tothe upper (127-1) or lower (127-3) main trunk. Cardiac branch electrode125-2 may be used as a cathode to provide a second electrical signal tocardiac branch 127-2. An additional electrode to function as the anodemay be selected from one or more of the other electrodes in electrodeassembly 125, can 121, or a dedicated anode.

In some embodiments (FIGS. 1D, 1E), electrode assembly 125 may include amain trunk electrode pair comprising a cathode 125-1 a and an anode125-1 b for coupling to a main trunk of a vagus nerve 127. The maintrunk electrode pair 125-1 a, 125-1 b may be coupled to an upper maintrunk 127-1 of a vagus nerve (FIG. 1D), or to a lower main trunk 127-3(FIG. 1E) for delivering a first electrical signal. Without being boundby theory, it is believed that few or no vagal afferent fibers in thelower main trunk 127-3 pass into cardiac branch 127-2 and, accordingly,that effects of the first electrical signal on cardiac function may beminimized by coupling electrode pair 125-1 a and 125-1 b to the lowermain trunk 127-3 instead of upper main trunk 127-1. Cardiac effects mayalso be minimized by alternative embodiments in which the firstelectrical signal is applied to a lower main trunk 127-3 using a singleelectrode (e.g., 125-3, FIG. 1C) as a cathode and an anode that is notcoupled to the vagus nerve 127 (e.g., by using can 121 as an anode).

In some embodiments (FIGS. 1D, 1E), electrode assembly 125 may include acardiac branch electrode pair comprising a cathode 125-2 a and an anode125-2 b for coupling to a cardiac branch of a vagus nerve. The secondcardiac branch electrode pair may be used to provide a second electricalsignal to a cardiac branch of the nerve to affect the cardiac functionof the patient.

Referring again to FIGS. 1C-1E, a first electrical signal may beprovided to generate afferent action potentials in a main trunk of avagus nerve to modulate electrical activity of the patient's brainwithout significantly affecting the patient's heart rate. The secondelectrical signal may generate efferent action potentials to module thecardiac activity of the patient, and in particular to slow the patient'sheart rate (e.g., to treat an epilepsy patient having seizurescharacterized by ictal tachycardia) and maintain or restore asympathetic/parasympathetic balance to a non-pathological state. Thefirst electrical signal may be applied to the main trunk of the vagusnerve in a variety of ways, so long as at least one electrode is coupledto the main trunk as a cathode. As noted, the cathode may be coupled toeither an upper (127-1) or lower (127-3) main trunk, and an anode may beprovided by any of the other electrodes on the vagus nerve (e.g., 125-1b, 125-2 b, 125-3, FIGS. 1C-1E) or by a separate anode not coupled tothe vagus nerve (e.g., can 121). In one alternative embodiment, anelectrode 125-3 may be coupled to a lower main trunk 127-3 of the vagusnerve to function as an anode. In yet another embodiment, eachindividual electrode element in FIGS. 1A-E (e.g., 125-1, 125-2, 125-3,125-1 a, 125-1 g, 125-2 a, 125-2 b) may comprise an electrode paircomprising both an anode and a cathode. In an additional embodiment,each individual electrode element may comprise three electrodes (e.g.,one serving as cathode and the other two as anodes). Suitable electrodeassemblies are available from Cyberonics, Inc., Houston, Tex., USA asthe Model 302, PerenniaFlex and PerenniaDura electrode assemblies. Inview of the present disclosure, persons of skill in the art willappreciate that many electrode designs could be used in embodiments ofthe present disclosure including unipolar electrodes.

Embodiments of the present disclosure may comprise electrical signalswith either charge-balanced or non-charge-balanced pulses (e.g.,monopolar/monophasic, direct current (DC)). Charge-balanced pulsesinvolve a first phase in which the stimulation occurs (i.e., actionpotentials are induced in target nerve fibers), and a second phase inwhich the polarity of the electrodes are reversed (i.e., the stimulationphase cathode becomes the charge-balancing phase anode, and vice versa).The result is a pulse having two opposite-polarity phases of equalcharge, such that no net charge flows across the electrode during apulse. Charge-balancing is often used to avoid damage to the electrodesthat may result if a pulse results in a net charge flowing across theelectrodes.

In some instances, charge-balancing may involve a passive dischargephase as illustrated in, e.g., FIG. 1A of US Publication 2006/0173493,which is hereby incorporated by reference in its entirety. In passivecharge-balancing, the charge-balancing phase typically involves allowinga capacitor having a charge equal to the charge applied to the nerveduring the stimulation phase to discharge through the polarity-reversedelectrodes. Passive charge-balancing typically uses much lower initialcurrent than the stimulation phase, with the current declining to zeroover a much longer time period than the pulse width of the stimulationphase. A lower current is typically selected in the charge-balancingphase so as to avoid or minimize nerve recruitment during thecharge-balancing phase. In active charge-balancing, the charge-balancingphase is not accomplished by the passive discharge of a capacitor, butby providing a second phase having an opposite polarity but the samecharge magnitude (pulse width multiplied by current) as the first phase.As is usually the case with passive charge-balancing, activecharge-balancing typically involves a much lower current that is appliedover a longer time period than the stimulation phase, so as to avoidnerve recruitment. In some instances, however, the activecharge-balancing phase may be used as a second stimulation phase byselecting a current magnitude of the cathode in the charge-balancingphase (typically a second electrode, which may be the anode of theinitial stimulation phase) that is sufficient to generate actionpotentials in nerve fibers of the target tissue.

Embodiments of the present disclosure may be implemented using passivecharge balancing or active charge-balancing, and the latter may beprovided as a stimulation phase or a non-stimulation phase. Someembodiments may be implemented with non-charge-balanced pulses. Personsof skill in the art, having the benefit of the present disclosure, mayselect the type of charge balancing (if desired) based upon a number offactors including but not limited to whether or not the charge-balancingis intended to affect the cardiac cycle or not, whether afferent orefferent stimulation is desired, the number and location of availableelectrodes for applying the electrical signal, the fibers intended to berecruited during a particular phase and their physiological effects,among many other factors.

In the discussion of electrical signals in the present disclosure,unless otherwise stated, references to electrodes as cathodes or anodesrefers to the polarities of the electrodes during a stimulation phase ofa pulse, whether the pulse is a charge-balanced pulse or anon-charge-balanced pulse (e.g., monopolar/monophasic or DC). It will beappreciated that where charge-balanced pulses are employed, thepolarities will be reversed during a charge-balancing phase. Whereactive charge-balancing is used, cardiac effects may be furtheramplified or ameliorated, depending upon the location of the electrodesbeing used.

Returning to FIG. 1A, in some embodiments, a heart rate sensor 130,and/or a kinetic sensor 140 (e.g., a triaxial accelerometer) may beincluded in the system 100 to sense one or more of a cardiac signal ordata stream and a kinetic data stream of the patient. In one embodiment,the heart rate sensor may comprise a separate element 130 that may becoupled to generator 110 through header 116 as illustrated in FIG. 1A.In another embodiment, the electrodes 125-1, 125-2, 125-3 and/or the can121 may be used as sensing electrodes to sense heart rate. Anaccelerometer may be provided inside generator 110 in one embodiment tosense a kinetic signal (e.g., body movement) of the patient. One or moreof the heart rate sensor 130 and the kinetic sensor 140 may be used by aseizure detection algorithm in the system 100 to detect epilepticseizures. In alternative embodiments, other body signals (e.g., bloodpressure, brain activity, blood oxygen/CO₂ concentrations, temperature,skin resistivity, etc.) of the patient may be sensed and used by theseizure detection algorithm to detect epileptic seizures. Signalgenerator 110 may be implanted in the patient's chest in a pocket orcavity formed by the implanting surgeon below the skin (indicated byline 145, FIG. 1A).

Returning to FIGS. 1A and 1C, a first electrode 125-1 may be wrapped orotherwise electrically coupled to an upper main trunk 127-1 of a vagusnerve 127 of the patient, and a second electrode 125-2 may be wrapped orcoupled to a cardiac branch 127-2 of the vagus nerve. In one embodiment,a third electrode 125-3 may be coupled to a lower main trunk 127-3 ofthe vagus nerve below the cardiac branch 127-2 of the vagus nerve,instead of or in addition to first electrode 125-1 coupled to the uppermain trunk above the cardiac branch. In some embodiments, thirdelectrode 125-3 may be omitted. Electrode assembly 125 may be secured tothe nerve by a spiral anchoring tether 128 (FIG. 1C), which in oneembodiment does not include an electrode but in alternative embodimentsmay contain up to three electrodes that serve as cathode(s) and anode(s)in any possible combination. Lead assembly 122 may further be secured,while retaining the ability to flex, by a suture connection 130 tonearby tissue (FIG. 1C). In particular embodiments, any of first, secondand third electrodes 125-1, 125-2, and 125-3 may be used as either acathode or as an anode. In general, the foregoing electrodes may be usedas a cathode when the particular electrode is the closest electrode(among a plurality of electrodes) to the target organ (e.g., heart,brain, stomach, liver, etc.) to be stimulated. While a single electrode(e.g., 125-1, 125-2, or 125-3) is illustrated in connection with uppermain trunk 127-1, cardiac branch 127-2, and lower main trunk 127-3 inFIGS. 1A and 1C for simplicity, it will be appreciated that one or moreadditional electrodes can be provided on each of the foregoing neuralstructures to provide greater flexibility in stimulation.

In one embodiment, the open helical design of the electrodes 125-1,125-2, 125-3, is self-sizing, flexible, minimize mechanical trauma tothe nerve and allow body fluid interchange with the nerve. The electrodeassembly 125 preferably conforms to the shape of the nerve, providing alow stimulation threshold by allowing a large stimulation contact areawith the nerve. Structurally, the electrode assembly 125 comprises anelectrode ribbon (not shown) for each of electrodes 125-1, 125-2, 125-3,made of a conductive material such as platinum, iridium,platinum-iridium alloys, and/or oxides thereof. The electrode ribbonsare individually bonded to an inside surface of an elastomeric bodyportion of the spiral electrodes 125-1, 125-2, 125-3 (FIG. 1C), whichmay comprise spiral loops of a multi-loop helical assembly. Leadassembly 122 may comprise three distinct lead wires or a triaxial cablethat are respectively coupled to one of the conductive electroderibbons. One suitable method of coupling the lead wires to theelectrodes 125-1, 125-2, 125-3 comprises a spacer assembly such as thatdisclosed in U.S. Pat. No. 5,531,778, although other known couplingmethods may be used.

The elastomeric body portion of each loop may be composed of siliconerubber or other biocompatible elastomeric compounds, and the fourth loop128 (which may have no electrode in some embodiments) acts as theanchoring tether for the electrode assembly 125.

In one embodiment, electrical pulse generator 110 may be programmed withan external computer 150 using programming software known in the art forstimulating neural structures, and a programming wand 155 to facilitateradio frequency (RF) communication between the external computer 150(FIG. 1A) and the implanted pulse generator 110. In one embodiment, wand155 and software permit wireless, non-invasive communication with thegenerator 110 after surgical implantation. Wand 155 may be powered byinternal batteries, and provided with a “power on” light to indicatesufficient power for communications. Another indicator light may beprovided to show that data transmission is occurring between the wandand the generator. In other embodiments, wand 155 may be omitted, e.g.,where communications occur in the 401-406 MHz bandwidth for MedicalImplant Communication Service (MICS band).

In some embodiments of the disclosure, a body data stream may beanalyzed to determine whether or not a seizure has occurred. Manydifferent body data streams and seizure detection indices have beenproposed for detecting epileptic seizures. Additional details on methodof detecting seizure from body data are provided in U.S. Pat. Nos.8,337,404 and 8,382,667, both issued in the name of the presentapplicant and both entitled, “Detecting, Quantifying, and/or ClassifyingSeizures Using Multimodal Data,” as well as in co-pending U.S. patentapplication Ser. No. 13/288,886, filed Nov. 3, 2011, each herebyincorporated by reference in its entirety herein. Seizure detectionbased on the patient's heart rate (as sensed by implanted or externalelectrodes), movement (as sensed by, e.g., a triaxial accelerometer),responsiveness, breathing, blood oxygen saturation, skinresistivity/conductivity, temperature, brain activity, and a number ofother body data streams are provided in the foregoing patents andco-pending applications.

In one embodiment, the present disclosure provides a method for treatinga patient with epilepsy in which a body data stream is analyzed using aseizure detection algorithm to determine whether or not the patient hashad an epileptic seizure. As used herein, the term “has had an epilepticseizure” includes instances in which a seizure onset has been detected,as well as instances in which the seizure onset has been detected andthe seizure is still ongoing (i.e., the seizure has not ended). If theanalysis results in a determination that the patient has not had anepileptic seizure, a signal generator may apply a first electricalsignal to a main trunk of a vagus nerve of the patient. If the analysisresults in a determination that the patient has had an epilepticseizure, the signal generator may apply a second electrical signal to acardiac branch of a vagus nerve of the patient. In some embodiments, theapplication of the first electrical signal to the main trunk isterminated, and only the second electrical signal to the cardiac branchis provided once a seizure is detected.

In alternative embodiments, both the first and second electrical signalsmay be applied to the main trunk and cardiac branch, respectively, ofthe vagus nerve in response to a determination that the patient has hada seizure (i.e., the first electrical signal continues to be applied tothe main trunk of the vagus nerve and the second signal is initiated).Where both the first and second electrical signals are provided, the twosignals may be provided sequentially, or in alternating fashion to themain trunk and the cardiac branch. In one embodiment, the first signalmay be provided to the main trunk by using one of the upper main trunkelectrode 125-1 or the lower main trunk electrode 125-3 as the cathodeand the cardiac branch electrode 125-2 as the anode, or by using both ofthe upper main trunk electrode and the lower main trunk electrode as thecathode and the anode. The second signal may be provided (e.g., byrapidly changing the polarity of the electrodes) by using the cardiacbranch electrode 125-2 as the cathode and a main trunk electrode 125-1or 125-3 as the anode.

In still other embodiments, the second electrical signal is applied tothe cardiac branch of the vagus nerve only if the analysis results in adetermination that the patient is having and/or has had an epilepticevent that is accompanied by an increase in heart rate, and the secondelectrical signal is used to lower the heart rate back towards a ratethat existed prior to the seizure onset. Without being bound by theory,the present inventors believe that slowing the heart rate at the onsetof seizures—particularly where the seizure is accompanied by an increasein heart rate—may improve the ability of VNS therapy to providecardio-protective benefits.

Prior patents describing vagus nerve stimulation as a medical therapyhave cautioned that undesired slowing of the heart rate may occur, andhave proposed various methods of avoiding such a slowing of the heartrate. In U.S. Pat. No. 6,341,236, it is suggested to sense heart rateduring delivery of VNS and if a slowing of the heart rate is detected,either suspending delivery of the VNS signal or pacing the heart using apacemaker. The present application discloses a VNS system that detectsepileptic seizures, particularly epileptic seizures accompanied by anincrease in heart rate, and intentionally applies an electrical signalto slow the heart rate in response to such a detection. In anotheraspect, the present application discloses VNS systems that provide afirst electrical signal to modulate only the brain during periods inwhich no seizure has been detected, and either 1) a second electricalsignal to modulate only the heart (to slow its rate) or 2) both a firstelectrical signal to the brain and a second electrical signal to theheart, in response to a detection of the onset of an epileptic seizure.These electrical signals may be delivered simultaneously, sequentially(e.g., delivery of stimulation to the brain precedes delivery ofstimulation to the heart or vice versa), or delivery of the first andsecond signals may be interspersed or interleaved.

The first electrode may be used as a cathode to provide an afferentfirst electrical signal to modulate the brain of the patient via maintrunk electrode 125-1. Electrode 125-1 may generate both afferent andefferent action potentials in vagus nerve 127. One or more of electrodes125-2 and 125-3 are used as anodes to complete the circuit. Where thisis the case, some of the action potentials may be blocked at theanode(s), with the result that the first electrical signal maypredominantly modulate the brain by afferent actions traveling towardthe brain, but may also modulate one or more other organs by efferentaction potentials traveling toward the heart and/or lower organs, to theextent that the efferent action potentials are not blocked by theanode(s).

The second electrode may be used as a cathode to provide an efferentsecond electrical signal to slow the heart rate of the patient viacardiac branch electrode 125-2. Either first electrode 125-1 or a thirdelectrode 125-3 (or can 121) may be used as an anode to complete thecircuit. In one embodiment, the first electrical signal may be appliedto the upper (127-1) or lower (127-3) main trunk of the vagus nerve inan open-loop manner according to programmed parameters including anoff-time and an on-time. The on-time and off-time together establish theduty cycle determining the fraction of time that the signal generatorapplies the first electrical. In one embodiment, the off-time may rangefrom 7 seconds to several hours or even longer, and the on-time mayrange from 5 seconds to 300 seconds. It should be noted that the dutycycle does not indicate when current is flowing through the circuit,which is determined from the on-time together with the pulse frequency(usually 10-200, Hz, and more commonly 20-30 Hz) and pulse width(typically 0.1-0.5 milliseconds). The first electrical signal may alsobe defined by a current magnitude (e.g., 0.25-3.5 milliamps), andpossibly other parameters (e.g., pulse width, and whether or not acurrent ramp-up and/or ramp-down is provided, a frequency, and a pulsewidth.

In one embodiment, a seizure detection may result in both applying thefirst electrical signal to provide stimulation to the brain in closeproximity to a seizure detection (which may interrupt or terminate theseizure), as well as application of the second electrical signal whichmay slow the heart, thus exerting a cardio-protective effect. In aparticular embodiment, the second electrical signal is applied only inresponse to a seizure detection that is characterized by (or accompaniedor associated with) an increase in heart rate, and is not applied inresponse to seizure detections that are not characterized by an increasein heart rate. In this manner, the second electrical signal may helpinterrupt the seizure by restoring the heart to a pre-seizure baselineheart rate when the patient experiences ictal tachycardia (elevatedheart rate during the seizure), while leaving the heart rate unchangedif the seizure has no significant effect on heart rate.

In still further embodiments, additional logical conditions may beestablished to control when the second electrical signal is applied tolower the patient's heart rate following a seizure detection. In oneembodiment, the second electrical signal is applied only if themagnitude of the ictal tachycardia rises above a defined level. In oneembodiment, the second electrical signal is applied to the cardiacbranch only if the heart rate increases by a threshold amount above thepre-ictal baseline heart rate (e.g., more than 20 beats per minute abovethe baseline rate). In another embodiment, the second electrical signalis applied to the cardiac branch only if the heart rate exceeds anabsolute heart rate threshold (e.g., 100 beats per minute, 120 beats perminute, or other programmable threshold). In a further embodiment, aduration constraint may be added to one or both of the heart rateincrease or absolute heart rate thresholds, such as a requirement thatthe heart rate exceed the baseline rate by 20 beats per minute for morethan 10 seconds, or exceed 110 beats per minute for more than 10seconds, before the second electrical signal is applied to the cardiacbranch in response to a seizure detection.

In another embodiment, the heart rate sensor continues to monitor thepatient's heart rate during and/or after application of the secondelectrical signal, and the second electrical signal is interrupted orterminated if the patient's heart rate is reduced below a low heart ratethreshold, which may be the baseline heart rate that the patientexperienced prior to the seizure, or a rate lower or higher than thebaseline pre-ictal heart rate. The low rate threshold may provide ameasure of safety to avoid undesired events such as bradycardia and/orsyncope.

In yet another embodiment, heart rate sensor 130 may continue to monitorheart rate and/or kinetic sensor 140 may continue to monitor bodymovement in response to applying the second electrical signal, and thesecond electrical signal may be modified (e.g., by changing one or moreparameters such as pulse frequency, or by interrupting and re-initiatingthe application of the second electrical signal to the cardiac branch ofthe vagus nerve) to control the heart rate below an upper heart ratethreshold and/or body movement exceeds one or more movement thresholds.For example, the frequency or duration of the second electrical signalapplied to the cardiac branch of the vagus nerve may be continuouslymodified based the instantaneous heart rate as monitored during thecourse of a seizure to control what would otherwise be an episode ofictal tachycardia below an upper heart rate threshold. In one exemplaryembodiment, the second electrical signal may be programmed to provide a30-second pulse burst at 30 Hz, with the pulses having a pulse width of0.25 milliseconds and a current of 1.5 milliamps. If, at the end of the30 second burst, the heart rate remains above 120 beats per minute, andis continuing to rise, the burst may be extended to 1 minute instead of30 seconds, the frequency may be increased to 50 Hz, the pulse width maybe increased to 350 milliseconds, or combinations of the foregoing. Instill further embodiments, additional therapies (e.g., oxygen delivery,drug delivery, cooling therapies, etc.) may be provided to the patientif the body data (heart rate, kinetic activity, etc.) indicates that thepatient's seizure is not under control or terminated.

Abnormalities or changes in EKG morphology or rhythm relative to aninterictal morphology or rhythm may also trigger delivery of current tothe heart via the trunks of vagi or its cardiac rami. In otherembodiments, pharmacological agents such as beta-blockers may beautomatically released into a patient's blood stream in response to thedetection of abnormal heart activity during or between seizures.

In one embodiment, the first electrical signal and the second electricalsignal are substantially identical. In another embodiment, the firstelectrical signal may vary from the second electrical signal in terms ofone or more of pulse width, number of pulses, amplitude, frequency,inter-pulse-interval, stimulation on-time, and stimulation off-time,among other parameters and degree, rate or type of charge balancing.

The number of pulses applied to the main trunk or cardiac branch,respectively, before changing the polarity of the first and secondelectrodes need not be one. Thus, two or more pulses may be applied tothe main trunk before applying pulses to the cardiac branch of the vagusnerve. More generally, the first and second signals can be independentof one another and applied according to timing and programmingparameters controlled by the controller 210 and stimulation unit 220.

In one embodiment, one or more pulse bursts of the first electricalsignal are applied to the main trunk of the vagus nerve in response to adetected seizure before applying one or more bursts of the secondelectrical signal to the cardiac branch. In another embodiment, thefirst and second signals are interleaved on a pulse-by-pulse basis underthe control of the controller 210 and stimulation unit 220.

Typically, VNS can be performed with pulse frequency of 20-30 Hz(resulting in a number of pulses per burst of 140-1800, at a burstduration from 7-60 sec). In one embodiment, at least one of the firstelectrical signal and the second electrical signal comprises amicroburst signal. Microburst neurostimulation is discussed by U.S. Ser.No. 11/693,451, filed Mar. 2, 2007 and published as United States patentPublication No. 20070233193, and incorporated herein by reference in itsentirety. In one embodiment, at least one of the first electricalsignal, the second electrical signal, and the third electrical signal ischaracterized by having a number of pulses per microburst from 2 pulsesto about 25 pulses, an interpulse interval of about 2 msec to about 50msec, an interburst period of at least 100 msec, and a microburstduration of less than about 1 sec.

Cranial nerves such as the vagus nerve include different types of nervefibers, such as A-fibers, B-fibers and C-fibers. The different fibertypes propagate action potentials at different velocities. Each nervefiber is directional—that is, endogenous or natural action potentialscan generally propagate action potentials in only one direction (e.g.,afferently to the brain or efferently to the heart and/or viscera). Thatdirection is referred to as the orthodromic direction. Exogenousstimulation (e.g., by electrical pulses) may induce action potentials inboth the orthodromic direction as well as the antidromic direction.Depending upon the desired effects of stimulation (e.g., afferentmodulation of the brain, efferent modulation of the heart, etc.) certainmeasures (e.g., cooling, pressure, etc.) may be taken to blockpropagation in either the efferent or the afferent direction. It isbelieved that the anode may block at least some action potentialstraveling to it from the cathode. For example, referring to FIG. 1 ,both afferent and efferent action potentials may be generated in anupper main trunk of vagus nerve 127-1 by applying a pulse to the nerveusing upper main trunk electrode 125-1 as a cathode. Action potentialsgenerated at upper main trunk electrode 125-1 and traveling toward theheart on cardiac branch 127-2 may be blocked by cardiac branch anode125-2. Action potentials traveling from the upper main trunk 127-1 tothe lower organs in lower main trunk 127-3 may be either blocked (byusing lower main trunk electrode 125-3 as an anode either with orinstead of cardiac branch electrode 125-2) or allowed to travel to thelower organs (by not using electrode structure 125-3 as an electrode).

Action potentials may be generated and allowed to travel to the heart bymaking the electrode 125-2 the cathode. If cardiac branch electrode125-2 is used as a cathode, action potentials will reach the heart inlarge numbers, while action potentials traveling afferently toward thebrain may be blocked in the upper trunk if upper electrode 125-1 is madethe anode.

In a further embodiment of the disclosure, rapid changes in electrodepolarity may be used to generate action potentials to collision blockaction potentials propagating in the opposite direction. To generalize,in some embodiments, the vagus nerve can be selectively stimulated topropagate action potentials either afferently (i.e., to the brain) orefferently (i.e., to the heart and/or lower organs/viscerae).

Turning now to FIG. 2 , a block diagram depiction of an implantablemedical device, in accordance with one illustrative embodiment of thepresent disclosure is illustrated. The IMD 200 may be coupled to variouselectrodes 125 and/or 127 via lead(s) 122 (FIGS. 1A, 1C). First andsecond electrical signals used for therapy may be transmitted from theIMD 200 to target areas of the patient's body, specifically to variouselectrodes associated with the leads 122. Stimulation signals from theIMD 200 may be transmitted via the leads 122 to stimulation electrodes(electrodes that apply the therapeutic electrical signal to the targettissue) associated with the electrode assembly 125, e.g., 125-1, 125-2,125-3 (FIG. 1A).

The IMD 200 may comprise a controller 210 capable of controlling variousaspects of the operation of the IMD 200. The controller 210 is capableof receiving internal data and/or external data and controlling thegeneration and delivery of a stimulation signal to target tissues of thepatient's body. For example, the controller 210 may receive manualinstructions from an operator externally, may perform stimulation basedon internal calculations and programming, and may receive and/or processsensor data received from one or more body data sensors such aselectrodes 125-1, 125-2, 125-3, or heart rate sensor 130. The controller210 is capable of affecting substantially all functions of the IMD 200.

The controller 210 may comprise various components, such as a processor215, a memory 217, etc. The processor 215 may comprise one or more microcontrollers, microprocessors, etc., that are capable of executing avariety of software components. The processor may receive, pre-conditionand/or condition sensor signals, and may control operations of othercomponents of the IMD 200, such as stimulation unit 220, seizuredetection module 240, logic unit 250, communication unit, 260, andelectrode polarity reversal unit 280. The memory 217 may comprisevarious memory portions, where a number of types of data (e.g., internaldata, external data instructions, software codes, status data,diagnostic data, etc.) may be stored. The memory 217 may store varioustables or other database content that could be used by the IMD 200 toimplement the override of normal operations. The memory 217 may compriserandom access memory (RAM) dynamic random access memory (DRAM),electrically erasable programmable read-only memory (EEPROM), flashmemory, etc.

The IMD 200 may also comprise a stimulation unit 220. The stimulationunit 220 is capable of generating and delivering a variety of electricalsignal therapy signals to one or more electrodes via leads. Thestimulation unit 220 is capable of delivering a programmed, firstelectrical signal to the leads 122 coupled to the IMD 200. Theelectrical signal may be delivered to the leads 122 by the stimulationunit 220 based upon instructions from the controller 210. Thestimulation unit 220 may comprise various types of circuitry, such asstimulation signal generators, impedance control circuitry to controlthe impedance “seen” by the leads, and other circuitry that receivesinstructions relating to the type of stimulation to be performed.

Signals from sensors (electrodes that are used to sense one or more bodyparameters such as temperature, heart rate, brain activity, etc.) may beprovided to the IMD 200. The body signal data from the sensors may beused by a seizure detection algorithm embedded or processed in seizuredetection module 240 to determine whether or not the patient is havingand/or has had an epileptic seizure. The seizure detection algorithm maycomprise hardware, software, firmware or combinations thereof, and mayoperate under the control of the controller 210. Although not shown,additional signal conditioning and filter elements (e.g., amplifiers,D/A converters, etc., may be used to appropriately condition the signalfor use by the seizure detection module 240. Sensors such as heartsensor 130 and kinetic sensor 140 may be used to detect seizures, alongwith other autonomic, neurologic, or other body data.

The IMD 200 may also comprise an electrode polarity reversal unit 280.The electrode polarity reversal unit 280 is capable of reversing thepolarity of electrodes (125-1, 125-2, 125-3) associated with theelectrode assembly 125. The electrode polarity reversal unit 280 isshown in more detail in FIG. 3 . In preferred embodiments, the electrodepolarity reversal unit is capable of reversing electrode polarityrapidly, i.e., in about 10 microseconds or less, and in any event at asufficiently rapid rate to permit electrode polarities to be changedbetween adjacent pulses in a pulsed electrical signal.

The IMD 200 may also comprise a power supply 230. The power supply 230may comprise a battery, voltage regulators, capacitors, etc., to providepower for the operation of the IMD 200, including delivering thestimulation signal. The power supply 230 comprises a power-sourcebattery that in some embodiments may be rechargeable. In otherembodiments, a non-rechargeable battery may be used. The power supply230 provides power for the operation of the IMD 200, includingelectronic operations and the stimulation function. The power supply 230may comprise a lithium/thionyl chloride cell or a lithium/carbonmonofluoride (LiCFx) cell. Other battery types known in the art ofimplantable medical devices may also be used.

The IMD 200 also comprises a communication unit 260 capable offacilitating communications between the IMD 200 and various devices. Inparticular, the communication unit 260 is capable of providingtransmission and reception of electronic signals to and from an externalunit 270. The external unit 270 may be a device that is capable ofprogramming various modules and stimulation parameters of the IMD 200.In one embodiment, the external unit 270 comprises a computer systemthat is capable of executing a data-acquisition program. The externalunit 270 may be controlled by a healthcare provider, such as aphysician, at a base station in, for example, a doctor's office. Theexternal unit 270 may be a computer, preferably a handheld computer orPDA, but may alternatively comprise any other device that is capable ofelectronic communications and programming. The external unit 270 maydownload various parameters and program software into the IMD 200 forprogramming the operation of the implantable device. The external unit270 may also receive and upload various status conditions and other datafrom the IMD 200. The communication unit 260 may be hardware, software,firmware, and/or any combination thereof. Communications between theexternal unit 270 and the communication unit 260 may occur via awireless or other type of communication, illustrated generally by line275 in FIG. 2 .

In one embodiment, the communication unit 260 can transmit a log ofstimulation data and/or seizure detection data to the patient, aphysician, or another party.

In one embodiment, a method of treating an epileptic seizure is providedthat involves providing simultaneously both a first electrical signal toa main trunk of a vagus nerve and a second electrical signal to acardiac branch of the vagus nerve. As used herein “simultaneously”refers to the on-time of the first and second signals, and does notrequire that individual pulses of the first signal and the second signalbe simultaneously applied to target tissue. The timing of pulses for thefirst electrical signal and the second electrical signal may bedetermined by controller 210 in conjunction with stimulation unit 220.Where active charge-balancing is used, it may be possible to use theactive charge-balancing phase of pulses of the first electrical signalas the stimulation phase of the second electrical signal by selecting acurrent magnitude of the cathode in the charge-balancing phase(typically a second electrode, which may be the anode of the initialstimulation phase) that is sufficient to generate action potentials innerve fibers of the target tissue. Controller 210 may in someembodiments provide simultaneous delivery of first and second electricalsignals by interleaving pulses for each of the first and secondelectrical signals based upon the programmed timing of pulses for eachsignal and the appropriate polarity of each of first and secondelectrodes 125-1 and 125-2. In some embodiments, additional electrodesmay be used to minimize the induction of action potentials to the heartor the brain provided by the first electrical signal or the secondelectrical signal. This may be accomplished, in one embodiment, by usingan anode located on either the upper main trunk or the cardiac branch toblock impulse conduction to the heart or brain from the cathode, or byproviding dedicated electrode pairs on both the main trunk and cardiacbranches (FIGS. 1D, 1E). When beneficial, steps to avoid collisions ofactions potentials travelling in opposite directions may be implemented,while steps to promote collisions may be taken when clinicallyindicated.

In some embodiments, the method further includes sensing a cardiacsignal and a kinetic signal of the patient, and detecting a seizureevent with a seizure detection algorithm.

In one embodiment, a first electrical signal is applied to a main trunkof a vagus nerve and a second electrical signal is simultaneouslyapplied to a cardiac branch of a vagus nerve. A pulse of the firstelectrical signal is generated with the electrical signal generator 110and applied to the main trunk of the vagus nerve using a first electrode(e.g., 125-1, 125-1 a) as a cathode and a second electrode (e.g., 125-1b, 125-3, or 125-2) as an anode. The method includes sensing a cardiacsignal and a kinetic signal of the patient, and detecting a seizureevent with a seizure detection algorithm. A pulse of the secondelectrical signal (having the appropriate pulse width and current) isgenerated and applied (under appropriate timing control by controller110 and stimulation unit 220) to the cardiac branch of the vagus nerveusing a second electrode (e.g., 125-2. 125-2 a) as a cathode and anotherelectrode (e.g., 125-3, 125-1, 125-2 b) as an anode. Another pulse ofthe first electrical signal may thereafter be generated and applied tothe main trunk under timing and parameter control of controller 210 andstimulation unit 220. By appropriate selection of cathodes and anodes,the first and second electrical signals may be interleaved and providedsimultaneously to the main trunk and cardiac branches of the vagusnerve. In some embodiments, the number of electrodes may be minimized byprovided a polarity reversal unit that may rapidly change the polarityof particular electrodes to allow their use in delivering both the firstand second signals.

The IMD 200 is capable of delivering stimulation that can be contingent,periodic, random, coded, and/or patterned. The stimulation signals maycomprise an electrical stimulation frequency of approximately 0.1 to10,000 Hz. The stimulation signals may comprise a pulse width in therange of approximately 1-2000 micro-seconds. The stimulation signals maycomprise current amplitude in the range of approximately 0.1 mA to 10mA. Appropriate precautions may be taken to avoid delivering injuriouscurrent densities to target neural tissues, e.g., by selecting current,voltage, frequency, pulse width, on-time and off-time parameters tomaintain current density below thresholds for damaging tissues.

The IMD 200 may also comprise a magnetic field detection unit 290. Themagnetic field detection unit 290 is capable of detecting magneticand/or electromagnetic fields of a predetermined magnitude. Whether themagnetic field results from a magnet placed proximate to the IMD 200, orwhether it results from a substantial magnetic field encompassing anarea, the magnetic field detection unit 290 is capable of informing theIMD of the existence of a magnetic field. The changeable electrodepolarity stimulation described herein may be activated, deactivated, oralternatively activated or deactivated using a magnetic input.

The magnetic field detection unit 290 may comprise various sensors, suchas a Reed Switch circuitry, a Hall Effect sensor circuitry, and/or thelike. The magnetic field detection unit 290 may also comprise variousregisters and/or data transceiver circuits that are capable of sendingsignals that are indicative of various magnetic fields, the time periodof such fields, etc. In this manner, the magnetic field detection unit290 is capable of detecting whether the detected magnetic field relatesto an input to implement a particular first or second electrical signal(or both) for application to the main trunk of cardiac branches,respectively, of the vagus nerve.

One or more of the blocks illustrated in the block diagram of the IMD200 in FIG. 2 , may comprise hardware units, software units, firmwareunits, or any combination thereof. Additionally, one or more blocksillustrated in FIG. 2 may be combined with other blocks, which mayrepresent circuit hardware units, software algorithms, etc.Additionally, one or more of the circuitry and/or software unitsassociated with the various blocks illustrated in FIG. 2 may be combinedinto a programmable device, such as a field programmable gate array, anASIC device, etc.

FIG. 3 shows in greater detail an electrode polarity reversal unit 280(FIG. 2 ) in one embodiment. The electrode polarity reversal unit 280comprises an electrode configuration switching unit 340, which includesa switching controller 345. The switching controller 345 transmitssignals to one or more switches, generically, n switches 330(1), 330(2),. . . 330(n) which effect the switching of the configuration of two ormore electrodes, generically, n electrodes 125(1), 125(2), . . . 125(n).Although FIG. 3 shows equal numbers of switches 330 and electrodes 125,persons of skill in the art having the benefit of the present disclosurewill understand that the number of switches 330 and their connectionswith the various electrodes 125 can be varied as a matter of routineoptimization. A switching timing unit 333 can signal to the electrodeconfiguration switching unit 340 that a desired time for switching theelectrode configuration has been reached.

Instructions for implementing two or more stimulation regimens, whichmay include at least one open-loop electrical signal and at least oneclosed-loop electrical signal, may be stored in the IMD 200. Thesestimulation signals may include data relating to the type of stimulationsignal to be implemented. In one embodiment, an open-loop signal may beapplied to generate action potentials for modulating the brain of thepatient, and a closed-loop signal may be applied to generate eitheraction potentials for slowing the heart rate of the patient, or bothaction potentials to modulate the brain of the patient as well as actionpotentials for slowing the heart rate of the patient. In someembodiments, the open-loop and closed-loop signals may be provided todifferent target portions of a vagus nerve of the patient by switchingthe polarity of two or more electrodes using an electrode polarityreversal unit as described in FIG. 3 above. In alternative embodiments,additional electrodes may be provided to generate each of the open-loopand closed-loop signals without electrode switching.

In one embodiment, a first open-loop mode of stimulation may be used toprovide an electrical signal to a vagus nerve using a first electrode asa cathode on a main trunk (e.g., 127-1 or 127-3 using electrodes 125-1or 125-3, respectively) of a vagus nerve, and a second electrode as ananode on either a main trunk (e.g., electrode 125-3, when electrode125-1 is used as a cathode) or cardiac branch (e.g., electrode 125-2) ofa vagus nerve. The first open-loop signal may include a programmedon-time and off-time during which electrical pulses are applied (theon-time) and not-applied (the off-time) in a repeating sequence to thevagus nerve.

A second, closed-loop signal may be provided in response to a detectedevent (such as an epileptic seizure, particularly when accompanied by anincrease in the patient's heart rate) using a different electrodeconfiguration than the first, open-loop signal. In one embodiment, thesecond, closed-loop signal is applied to a cardiac branch using thesecond electrode 125-2 as a cathode and the first electrode on the maintrunk (e.g., 125-1 or 125-3) as an anode. The second, closed-loop signalmay involve generating efferent action potentials on the cardiac branchof the vagus nerve to slow the heart rate. In some embodiments, thefirst, open-loop signal may be interrupted/suspended in response to thedetected event, and only the second, closed-loop signal is applied tothe nerve. In other embodiments, the first, open loop signal may not beinterrupted when the event is detected, and both the first, open-loopsignal and the second, closed-loop signal are applied to the vagusnerve. In another embodiment, a third, closed-loop signal may also beprovided in response to the detected event. The third, closed-loopsignal may involve an electrical signal using the same electrodeconfiguration as the first, open-loop electrical signal, but may providea different electrical signal to the main trunk of the vagus nerve thaneither the first, open-loop signal or the second, closed-loop signal.The first, open-loop signal may be interrupted, terminated or suspendedin response to the detected event, and the third, closed-loop signal maybe applied to the nerve either alone or with the second, closed-loopsignal. In some embodiments, both the second and third closed-loopsignals may be provided in response to a detected epileptic seizure byrapidly changing the polarity of the first (125-1) and second (125-2)electrodes from cathode to anode and back, as pulses are provided aspart of the second and third electrical signals, respectively. In oneembodiment, the third electrical signal may involve modulating the brainby using a main trunk electrode (e.g., upper main trunk electrode 125-1)as a cathode and another electrode (e.g., cardiac branch electrode 125-2or lower main trunk electrode 125-3) as an anode. The third electricalsignal may comprise, for example, a signal that is similar to the firstelectrical signal but which provides a higher electrical current thanthe first electrical signal, and for a longer duration than the firstsignal or for a duration that is adaptively determined based upon asensed body signal (in contrast, for example, to a fixed duration of thefirst electrical signal determined by a programmed on-time). By rapidlychanging polarity of the electrodes, pulses for each of the second andthird electrical signals may be provided such that the second and thirdsignals are provided simultaneously to the cardiac branch and main trunkof the vagus nerve. In other embodiments, the first, second and thirdelectrical signals may be provided sequentially rather thansimultaneously.

In some embodiments, one or more of the first, second and thirdelectrical signals may comprise a microburst signal, as described morefully in U.S. patent application Ser. Nos. 11/693,421, 11/693,451, and11/693,499, each filed Mar. 29, 2007 and each hereby incorporated byreference herein in their entirety.

In one embodiment, each of a plurality of stimulation regimens mayrespectively relate to a particular disorder, or to particular eventscharacterizing the disorder. For example, different electrical signalsmay be provided to one or both of the main trunk and cardiac branches ofthe vagus nerve depending upon what effects accompany the seizure. In aparticular embodiment, a first open-loop signal may be provided to thepatient in the absence of a seizure detection, while a second,closed-loop signal may be provided when a seizure is detected based on afirst type of body movement of the patient as detected by, e.g., anaccelerometer, a third, closed-loop signal may be provided when theseizure is characterized by a second type of body movement, a fourth,closed-loop signal may be provided when the seizure is characterized byan increase in heart rate, a fifth, closed-loop signal may be providedwhen the seizure is characterized by a decrease in heart rate, and soon. More generally, stimulation of particular branches or main trunktargets of a vagus nerve may be provided based upon different bodysignals of the patient. In some embodiments, additional therapies may beprovided based on different events that accompany the seizure, e.g.,stimulation of a trigeminal nerve or providing a drug therapy to thepatient through a drug pump. In one embodiment, different regimensrelating to the same disorder may be implemented to accommodateimprovements or regressions in the patient's present condition relativeto his or her condition at previous times. By providing flexibility inelectrode configurations nearly instantaneously, the present disclosuregreatly expands the range of adjustments that may be made to respond tochanges in the patient's underlying medical condition.

The switching controller 345 may be a processor that is capable ofreceiving data relating to the stimulation regimens. In an alternativeembodiment, the switching controller may be a software or a firmwaremodule. Based upon the particulars of the stimulation regimens, theswitching timing unit 333 may provide timing data to the switchingcontroller 345. The first through nth switches 330(1-n) may beelectrical devices, electro-mechanical devices, and/or solid statedevices (e.g., transistors).

FIG. 4 shows one embodiment of a method of treating a patient havingepilepsy according to the present disclosure. In this embodiment, afirst electrode is coupled to a main trunk of a vagus nerve of thepatient (410) and a second electrode is coupled to a cardiac branch ofthe vagus nerve (420). An electrical signal generator is coupled to thefirst and second electrodes (430).

The method further involves receiving at least one body data stream ofthe patient (440). The data may be sensed by a sensor such as heart ratesensor 130 (FIG. 1A) or a sensor that is an integral part of, or coupledto, an IMD 200 (FIG. 2 ) such as electrical pulse generator 110 (FIG.1A), and the IMD may also receive the data from the sensor. The at leastone body data stream is then analyzed using a seizure detectionalgorithm (450), and the seizure detection algorithm determines whetheror not the patient is having and/or has had an epileptic seizure (460).

If the algorithm indicates that the patient is not having and/or has nothad an epileptic seizure, the method comprises applying a firstelectrical signal from the electrical signal generator to the main trunkof a vagus nerve using the first electrode as a cathode (470). In oneembodiment, applying the first electrical signal comprises continuing toapply a programmed, open-loop electrical signal periodically to the maintrunk of the vagus nerve according a programmed on-time and off-time.

If the algorithm indicates that the patient is having and/or has had anepileptic seizure, the method comprises applying a second electricalsignal from the electrical signal generator to the cardiac branch of thevagus nerve using the second electrode as a cathode (480). Dependingupon which electrical signal (first or second) is applied, the methodmay involve changing the polarity of one or both of the first electrodeand the second electrode. In one embodiment, the method may comprisesuspending the first electrical and applying the second electricalsignal. In one embodiment, the method comprises continuing to receive atleast one body data stream of the patient at 440 after determiningwhether or not the patient is having and/or has had an epilepticseizure.

In an alternative embodiment, if the seizure detection algorithmindicates that the patient is having and/or has had an epilepticseizure, both the first electrical signal and the second electricalsignal are applied to the main trunk and cardiac branches of a vagusnerve of the patient, respectively, at step 480. In a specificimplementation of the alternative embodiment, pulses of the first andsecond electrical signal are applied to the main trunk and cardiacbranch of the vagus nerve under the control of controller 210 by rapidlychanging the polarity of the first and second electrodes using theelectrode polarity reversal unit 280 to apply the first electricalsignal to the main trunk using the first electrode as a cathode and thesecond electrode as an anode, changing the polarity of the first andsecond electrodes, and applying the second electrical signal to thecardiac branch using the second electrode as a cathode and the firstelectrode as an anode. Additional pulses for each signal may besimilarly applied by rapidly changing the polarity of the electrodes.

In some embodiments, the first electrical signal and the secondelectrical signal are applied unilaterally, i.e., to a vagal main trunkand a cardiac branch on the same side of the body. In other embodiments,the first and second electrical signals are applied bilaterally, i.e.,the second electrical signal is applied to a cardiac branch on theopposite side of the body from the main vagal trunk to which the firstelectrical signal is applied. In one embodiment, the first electricalsignal is applied to a left main trunk to minimize cardiac effects ofthe first electrical signal, and the second electrical signal is appliedto a right cardiac branch, which modulates the sinoatrial node of theheart to maximize cardiac effects of the second electrical signal.

In alternative embodiments, both the first electrode and the secondelectrode may be coupled to a cardiac branch of a vagus nerve, with thefirst electrode (e.g., anode) being proximal to the brain relative tothe second electrode, and the second electrode (e.g., cathode) beingproximal to the heart relative to the first electrode.

FIG. 5 is a flow diagram of another method of treating a patient havingepilepsy according to the present disclosure. A sensor is used to sensea cardiac signal and a kinetic signal of the patient (540). In aparticular embodiment, the cardiac sensor may comprise an electrode pairfor sensing an ECG (electrocardiogram) or heart beat signal, and thekinetic signal may comprise a triaxial accelerometer to detect motion ofat least a portion of the patient's body. The method further comprisesanalyzing at least one of the cardiac signal and the kinetic signalusing seizure detection algorithm (550), and the output of the algorithmis used to determine whether at least one of the cardiac signal and thekinetic signal indicate that the patient is having and/or has had anepileptic seizure (560).

If the patient is not having and/or has not had an epileptic seizure,the method comprises applying a first electrical signal to a main trunkof a vagus nerve of the patient using a first electrode, coupled to themain trunk, as a cathode (580). In one embodiment, the first electricalsignal is an open-loop electrical signal having an on-time and off-time.

If the patient is having and/or has had an epileptic seizure, adetermination is made whether the seizure is characterized by anincrease in the patient's heart rate (570). If the seizure is notcharacterized by an increase in the patient's heart rate, the methodcomprises applying the first electrical signal to the main trunk of avagus nerve using the first electrode as a cathode (580). In oneembodiment, the cathode comprises an upper main trunk electrode 125-1and the anode is selected from a cardiac branch electrode 125-2 and alower main trunk electrode 125-3. Conversely, if the seizure ischaracterized by an increase in the patient's heart rate, the methodcomprises applying a second electrical signal to a cardiac branch of avagus nerve of the patient using a second electrode, coupled to thecardiac branch, as a cathode (590). The anode is an upper main trunkelectrode 125-1 or a lower main trunk electrode 125-3. In oneembodiment, the method may comprise suspending the first electrical andapplying the second electrical signal.

The method then continues the sensing of the cardiac and kinetic signalsof the patient (540) and resumes the method as outlined in FIG. 5 .

FIG. 6 is a flow diagram of a further method of treating a patienthaving epilepsy according to the present disclosure. The method includesapplying a first, open-loop electrical signal to a main trunk of a vagusnerve (610). The open-loop signal is characterized by an off-time inwhich electrical pulses are applied to the nerve, and an off-time inwhich electrical pulses are not applied to the nerve.

A sensor is used to sense at least one body signal of the patient (620),and a determination is made whether the at least one body signalindicates that the patient is having and/or has had an epileptic seizure(630). If the patient is not having and/or has not had a seizure, themethod continues applying the first, open-loop electrical signal to amain trunk of a vagus nerve (610). If the patient is having and/or hashad an epileptic seizure, a determination is made whether the seizure ischaracterized by an increase in the patient's heart rate (640). In oneembodiment, the increase in heart rate is measured from a baseline heartrate existing prior to the seizure, e.g., a median heart rate for aprior period such as the 300 beats prior to the detection of the seizureevent, or the 5 minutes prior to the detection of the seizure.

If the seizure is not characterized by an increase in the patient'sheart rate, the method comprises applying a second, closed-loopelectrical signal to the main trunk of the vagus nerve 650). In oneembodiment, the second, closed-loop electrical signal is the same signalas the open-loop electrical signal, except that the second signal (asdefined, e.g., by a current intensity, a pulse frequency, a pulse widthand an on-time) is applied at a time different from the programmedtiming of the first electrical signal. For example, if the firstelectrical signal comprises an on-time of 30 seconds and an off-time of5 minutes, but a seizure is detected 1 minute after the end of aprogrammed on-time, the second electrical signal may comprise applying a30 second pulse burst at the same current intensity, frequency, andpulse width as the first signal, but four minutes earlier than wouldhave occurred absent the detected seizure. In another embodiment, thesecond, closed-loop electrical signal is a different signal than thefirst, open-loop electrical signal, and the method may also comprisesuspending the first electrical before applying the second electricalsignal. For example, the second, closed-loop electrical signal maycomprise a higher current intensity, frequency, pulse width and/oron-time than the first, open-loop electrical signal, and may notcomprise an off-time (e.g., the second electrical signal may be appliedfor a predetermined duration independent of the on-time of the first,open-loop electrical signal, such as a fixed duration of 1 minute, ormay continue for as long as the body signal indicates the presence ofthe seizure event).

Returning to FIG. 6 , if the seizure is characterized by an increase inthe patient's heart rate, the method comprises applying a third,closed-loop electrical signal to a cardiac branch of a vagus nerve toreduce the patient's heart rate (660). The method may comprisesuspending the first electrical as well as applying the third,closed-loop electrical signal. In one embodiment of the disclosure, eachof the first, open-loop electrical signal, the second, closed-loopelectrical signal, and the third, closed-loop electrical signal areapplied unilaterally (i.e., to vagus nerve structures on the same sideof the body) to the main trunk and cardiac branch of the vagus nerve.For example, the first, open-loop electrical signal and the second,closed-loop electrical signal may be applied to a left main trunk of thepatient's cervical vagus nerve, and the third, closed-loop electricalsignal may be applied to the left cardiac branch of the vagus nerve.Similarly, the first, second and third electrical signals may all beapplied to the right vagus nerve of the patient. In alternativeembodiments, one or more of the first, second and third electricalsignals may be applied bilaterally, i.e., one of the first, second andthird electrical signals is applied to a vagal structure on the oppositeside of the body from the other two signals. For example, in aparticular embodiment the first, open-loop signal and the second,closed-loop signal may be applied to a left main trunk of the patient'scervical vagus nerve, and the third, closed-loop electrical signal maybe applied to a right cardiac branch of the patient's vagus nerve.Because the right cardiac branch modulates the sinoatrial node of thepatient's heart, which is the heart's “natural pacemaker,” the thirdelectrical signal may have more pronounced effect in reducing thepatient's heart rate if applied to the right cardiac branch.

After applying one of the second (650) and third (660) electricalsignals to a vagus nerve of the patient, the method then continuessensing at least one body signal of the patient (620) and resumes themethod as outlined in FIG. 6 .

In the methods depicted in FIGS. 4-6 , one or more of the parametersdefining the first, second, and third electrical signals (e.g., numberof pulses, pulse frequency, pulse width, On time, Off time, interpulseinterval, number of pulses per burst, or interburst interval, amongothers) can be changed by a healthcare provided using a programmer 150.

FIG. 7 is a flow diagram of a method of treating patients havingseizures accompanied by increased heart rate. In one embodiment,tachycardia is defined as a neurogenic increase in heart rate, that is,an elevation in heart rate that occurs in the absence of motor activityor that if associated with motor activity, the magnitude of the increasein heart rate is larger than that caused by motor activity alone. In oneembodiment, a body signal is acquired (710). The body signal maycomprise one or more body signals that may be altered, changed orinfluenced by an epileptic seizure. As non-limiting examples, the bodysignal may comprise one or more of a cardiac signal such as heart rate,heart rate variability, or EKG complex morphology, a kinetic signal suchas an accelerometer signal, a postural signal or body position signal),blood pressure, blood oxygen concentration, skin resistivity orconductivity, pupil dilation, eye movement, EEG, reaction time or otherbody signals. The body signal may be a real-time signal or a storedsignal for delayed or later analysis. It may be acquired, for example,from a sensor element (e.g., coupled to a processor), from a storagedevice in which the signal data is stored.

The method further comprises determining whether or not the patient ishaving and/or has had a seizure accompanied by an increase in heart rate(720). In one embodiment, the method comprises a seizure detectionalgorithm that analyzes the acquired body signal data and determineswhether or not a seizure has occurred. In a particular embodiment, themethod comprises an algorithm that analyzes one or more of a cardiacsignal, a kinetic signal, a cognitive signal, blood pressure, bloodoxygen concentration, skin resistivity or conductivity, pupil dilation,and eye movement to identify changes in the one or more signals thatindicate a seizure has occurred. The method may comprise an outputsignal or data flag that may be asserted or set when the detectionalgorithm determines from the body signal(s) that the patient is havingand/or has had a seizure.

The method also comprises determining (720) whether or not the seizureis accompanied by an increase in heart rate. In one embodiment, the bodydata signal comprises a heart beat signal that may be analyzed todetermine heart rate. In some embodiments, the heart beat signal may beused by the seizure detection algorithm to determine whether a seizurehas occurred, while in other embodiments seizures are not detected usingheart rate. Regardless of how the seizure is detected, however, themethod of FIG. 7 comprises determining whether a detected seizure eventis accompanied by an increase in heart rate. The increase may bedetermined in a variety of ways, such as by an increase in aninstantaneous heart rate above a reference heart rate (which may be apredetermined interictal value such as 72 beats per minute (bpm), or areal-time measure of central tendency for a time window, such as a 5minute median or moving average heart rate). Additional details aboutidentifying increases in heart rate in the context of epileptic seizuresare provided in U.S. Pat. Nos. 5,928,272, 6,341,236, 6,587,727,6,671,556, 6,961,618, 6,920,357, 7,457,665, as well as U.S. patentapplication Ser. Nos. 12/770,562, 12/771,727, 12/771,783, 12/884,051,12/886,419, 12/896,525, 13/098,262, and 13/288,886, each of which ishereby incorporated by reference in its entirety herein.

If the body data signal does not indicate that the patient is havingand/or has had a seizure accompanied by tachycardia, the methodcomprises applying a first electrical signal to a left vagus nerve. Ifthe body signal does indicate that the patient has experienced a seizureaccompanied by tachycardia, the method comprises applying a secondelectrical signal to a right vagus nerve.

Without being bound by theory, it is believed that stimulation of theright vagus nerve, which enervates the right sinoatrial nerve thatfunctions as the heart's natural pacemaker, will have a more prominenteffect in slowing the heart rate than stimulation of the left vagusnerve. The present disclosure takes advantage of this electricalasymmetry of the left and right vagus nerves to minimize the effect ofVNS on heart rate except where there is a need for acute intervention toslow the heart rate, i.e., when the patient has experienced andepileptic seizure, and the seizure is accompanied by an increase inheart rate. This may result in, for example, stimulation of the leftvagus nerve either when there is no seizure (such as when an open-loopstimulation program off-time has elapsed and the program initiatesstimulation in accordance with a programmed signal on-time), or whenthere is a detected seizure event that is not accompanied by an increasein heart rate (such as absence seizures); and stimulation of the rightvagus nerve when there is a detected seizure event accompanied by aheart rate increase. In one embodiment, a programmed, open-loopelectrical signal is applied to the left vagus nerve except when analgorithm analyzing the acquired body signal detects a seizureaccompanied by a heart rate increase. In response to such a detection, aclosed-loop electrical signal is applied to the right vagus nerve toslow the patient's (increased) heart rate. In some embodiments, theresponse to detecting a seizure accompanied by a heart rate increase mayalso include interrupting the application of the programmed-open-loopelectrical signal to the left vagus nerve. The interrupted open-loopstimulation of the left vagus nerve may be resumed either when theseizure ends or the heart rate returns to a desired, lower heart rate.

In an additional embodiment of the disclosure, electrode pairs may beapplied to each of the left and right vagus nerves of the patient, andused depending upon whether or not seizures accompanied by cardiacchanges such as tachycardia are detected.

FIG. 8 is a flowchart depiction of a method of treating patients havingseizures accompanied by a relative or absolute decrease in heart rate(i.e., a bradycardia episode). Epileptic seizures originating fromcertain brain regions may trigger decreases in heart rate of a magnitudesufficient to cause loss of consciousness and of postural tone (i.e.,syncope). In some subjects the cerebral ischemia associated with thebradycardia may in turn lead to convulsions (i.e., convulsive syncope).If bradycardia-inducing seizures are not controllable by medications,the current treatment is implantation of a demand cardiac pacemaker. Inone embodiment of the present disclosure, ictal bradycardia may betreated by preventing vagal nerve impulses from reaching the heart,either by preventing impulses traveling through all fiber typescontained in the trunk of the nerve or in one of its branches, or byonly blocking impulses within a certain fiber type. In anotherembodiment, the degree of the nerve impulse blocking within a vagusnerve may be determined based upon the magnitude of bradycardia (e.g.,the larger the bradycardia change from the pre-existing baseline heartrate, the larger the magnitude of the block) so as to preventtachycardia from occurring.

In one embodiment, a body signal is acquired (810). The body signal maycomprise one or more body signals that may be altered, changed orinfluenced by an epileptic seizure. Changes in the body signal may beused to detect the onset or impending onset of seizures. As noted withreference to FIG. 7 , the body signal may comprise one or more measurederived from a cardiac signal (e.g., heart rate, heart rate variability,change in EKG morphology), a kinetic signal (e.g., an accelerometer,force of muscle contraction, posture or body position signal), bloodpressure, blood oxygen concentration, skin resistivity/conductivity,pupil dilation, eye movement, or other body signals. The body signal maybe a real-time signal, a near-real-time signal, or a non-real-timesignal, although in preferred embodiments, the signal is a real-timesignal or a near-real-time signal. The signal may be acquired from asensor element (e.g., coupled to a processor) or from a storage device.

Referring again to FIG. 8 , the method further comprises determiningwhether or not the patient is having and/or has had a seizure that isaccompanied by a decrease in heart rate (820). In one embodiment, themethod comprises using a seizure detection algorithm using one or moreof a cardiac, kinetic, neurologic, endocrine, metabolic or tissue stressmarker to detect seizures, and to determine if the seizure is associatedwith a decrease in heart rate. In a particular embodiment, analgorithm—which may comprise software and/or firmware running in aprocessor in a medical device—analyzes one or more of a cardiac signal,a kinetic signal, blood pressure, blood oxygen concentration, skinresistivity or conductivity, pupil dilation, and eye movement toidentify changes in the one or more signals that indicate the occurrenceof an epileptic seizure. Such changes may be identified by determiningone or more indices from the foregoing signals, such as a cardiac index(e.g., a heart rate), a kinetic index (e.g., a kinetic level or motiontype, a magnitude of an acceleration or force, or other indices that maybe calculated from an accelerometer signal). The method may includeproviding an output signal or setting a data flag when the detectionalgorithm determines from the body signal(s) that the patient is havingand/or has had a seizure. In a preferred embodiment, the seizuredetection occurs in real time and the output signal or data flag is setimmediately upon detection of the seizure.

Once it is determined that the patient is having and/or has had aseizure, the method also comprises determining if the seizure isaccompanied by a decrease in heart rate. In one embodiment, the acquiredbody data signal (810) comprises a heart beat signal that may beanalyzed to determine heart rate. In some embodiments, the acquiredheart beat signal may be used by the seizure detection algorithm todetermine whether a seizure has occurred, while in other embodimentsseizures are determined without regard to the patient's heart rate.Regardless of how the seizure is determined, the method of FIG. 8comprises determining whether a detected seizure event is accompanied bya decrease in heart rate (820). The decrease in heart rate may bedetermined in a variety of ways, such as by a decrease in aninstantaneous heart rate below a reference heart rate value (which maybe a predetermined interictal value such as 72 beats per minute (bpm),or a real-time measure of central tendency for a time window ornumber-of-beats window (e.g., a 5 minute median or moving average heartrate, or a media heart rate for a window selected from 3-300 beats suchas a 5, 10, or 300 beat window)). Additional details about identifyingdecreases in heart rate in the context of epileptic seizures areprovided in U.S. patent application Ser. Nos. 12/770,562, 12/771,727,12/771,783, 12/884,051, 12/886,419, 13/091,033, each of which is herebyincorporated by reference in its entirety herein.

In one embodiment, if the acquired body data signal does not indicatethat the patient is having and/or has had a seizure accompanied by a HRdecrease, the method comprises applying a first electrical signal to avagus nerve (840), wherein the first electrical signal is sufficient togenerate exogenous action potentials in fibers of the vagus nerve. Thesecond electrical signal is a therapeutic electrical signal to treat theseizure. It may be applied to either the left or right vagus nerves, orboth. The first electrical signal may be a signal defined by, amongother parameters, an on-time during which electrical pulses are appliedto the nerve, and an off-time during which no pulses are applied to thenerve. In some embodiments, the on-time may be determined by theduration and intensity of the change in heart rate, while in otherembodiments it may be pre-programmed Cathode(s) and anode(s) may beplaced on the nerve trunks or branches to maximize flow of exogenouslygenerated nerve impulses in a caudal direction (for control of heartrate changes) and a cephalic direction for seizure treatment.

If the body signal indicates that the patient is having and/or has had aseizure accompanied by a decrease in heart rate, the method comprisesapplying an action to decrease vagal/parasympathetic tone. In oneembodiment, the method comprises blocking the passage of impulsesthrough at least one of a vagus nerve trunk or branch. This may beaccomplished by applying one or more of a second electrical signal(e.g., a high frequency electrical signal), a thermal signal (e.g.,cooling), a chemical signal (e.g., applying a local anesthetic), and/ora mechanical signal (e.g., applying pressure or a vibration) to a vagusnerve of the patient (830). In another embodiment, the method comprisesdelivering at least one of an anti-cholinergic drug or asympatho-mimetic drug.

As used herein, blocking vagus nerve activity means blocking intrinsicor native vagal activity (i.e., blocking action potentials notartificially or exogenously induced by an electrical signal generated bya device). The blocking signal may block the conduction of actionpotentials in all or at least some portion or fraction of the axons of avagus nerve. In general, such blocking signals are incapable of inducingexogenous action potentials in the axons of the vagus nerve. In oneembodiment, the blocking signal may comprise a high frequency, pulsedelectrical signal, the pulse frequency being sufficient to inhibitpropagation of at least some action potentials in vagus nerve fibers.The electrical signal may comprise a signal in excess of 300 Hz, orother frequency, so long as the frequency and other stimulation signalparameters (such as pulse width and pulse current or voltage) provide asignal capable of inhibiting some or all of the action potentialspropagating along fibers of the vagus nerve. In alternative embodiments,the electrical signal may comprise generating unidirectional actionpotentials for collision blocking of endogenous action potentials.

High frequency vagus nerve stimulation (or other blocking signals suchas collision blocking) may inhibit pathological vagus nerve activityassociated with the seizure that may be acting to slow the patient'sheart rate. By providing such stimulation only when the patientexperiences a seizure accompanied by a reduced heart rate (e.g.,bradycardia), a therapy may be provided that acts to maintain thepatient's heart rate when the patient experiences a seizure involvingexcessive vagal activity—and consequent undesired slowing of—the heart.In one embodiment, the blocking electrical signal (830) is provided to aright vagus nerve. Without being bound by theory, because the rightvagus nerve innervates the right sinoatrial node that functions as theheart's natural pacemaker, it is believed that right-side VNS will havea more significant effect upon the heart rate than stimulation of theleft vagus nerve. In alternative embodiments, the blocking signal may beapplied to the left vagus nerve, to both the right and left vagusnerves, or to one or both of the left and right cardiac branches of thevagus nerves.

In one embodiment, the method comprises applying a first electricalsignal that may be a conventional vagus nerve stimulation signal definedby a plurality of parameters (e.g., a pulse width, a current magnitude,a pulse frequency, an on-time and an off-time). A seizure detectionalgorithm (e.g., using one or more of a cardiac, kinetic, metabolic,EEG, or other body signal) may be used to detect seizures, and thepatient's heart rate may be determined proximate the seizure detectionto determine if the seizure is accompanied by a decrease in thepatient's heart rate. If the seizure is accompanied by a slowing of thepatient's heart rate, the first electrical signal may be suspended, anda second electrical signal may be applied to slow the patient's heartrate. The method may further include sensing the patient's heart rateduring or after application of the second electrical signal. In oneembodiment, the second electrical signal may be modified (e.g., bychanging current magnitude, pulse width, or pulse frequency), orsuspended (and possibly resumed) to maintain the patient's heart ratebetween an upper heart rate threshold and a lower heart rate threshold.In some embodiments, the upper and lower heart rate thresholds may bedynamically set (e.g., as no more than 5 bpm above or below the baselineHR prior to the seizure detection).

FIG. 9 is a flow diagram of a method of treating a patient with epilepsyby providing closed-loop vagus nerve intervention (e.g., stimulation orblockage of impulse conduction) to maintain the patient's heart ratewithin a range that is both safe and also commensurate with the activitytype or level and state of the patient (e.g., as determined from akinetic signal from a sensing element such as a triaxial accelerometeror by measuring oxygen consumption). In one embodiment, the methodcomprises providing vagus nerve stimulation in response to determiningthat a heart rate is incommensurate with the kinetic signal of thepatient, to restore cardiac function to a rate that is commensurate withthe patient's kinetic signal. In one embodiment, the stimulation maycomprise stimulating a right vagus nerve to slow the patient's heartrate to a level that is safe and/or commensurate with activity level. Inanother embodiment, the stimulation may comprise providing a blockingsignal to increase a slow heart rate to a rate that is safe and/orcommensurate with the activity level. Pharmacologic compounds (e.g.,drugs) with sympathetic or parasympathetic effects (e.g., enhancing orblocking sympathetic or parasympathetic activity) may be used to restoreheart rate to a rate commensurate with kinetic activity of the patientin still other embodiments. In one embodiment, the method involvesdetermining a heart rate and one or more kinetic or metabolic (e.g.,oxygen consumption) indices for the patient (910). Heart rate may bedetermined from an acquired cardiac signal (e.g., from a sensor orstored data). Kinetic and/or metabolic indices may likewise bedetermined from a kinetic sensor (e.g., an accelerometer, a positionalsensor, a GPS device coupled to a clock, or a postural sensor), ametabolic sensor, or from stored data. Sensor data may be subjected toone or more operations such as amplifying, filtering, A/D conversion,and/or other pre-processing and processing operations to enabledetermination of heart rate (and in some embodiments other cardiacindices such as heart rate variability) and kinetic indices.

The activity level of the patient may be determined from multiplekinetic indications such as an activity level, a type of activity, aposture, a body position, a trunk or limb acceleration or force, or aduration of one of the foregoing, and may be adapted or modified as afunction of age, gender, body mass index, fitness level or time of dayor other indices of the patient's condition or environment. For example,the kinetic signal may be processed to provide indices that indicatemoderate ambulatory motion for an upright patient, vigorous physicalexercise (in which the patient may be upright as in running or in aprone position as in some calisthenics exercises), a fall (e.g.,associated with a seizure), reclining, resting or sleeping, among otheractivity levels and kinetic states.

The one or more kinetic indices may then be used to determine (e.g., byretrieving stored data from a lookup table or by calculation using analgorithm) one or more heart rate ranges or values that would becommensurate with the kinetic activity and/or kinetic state, duration,time of day, etc. associated with the indices. In some embodiments,heart rate ranges may be established for particular levels or types ofactivity (e.g., running, walking), that may be adaptively adjusteddepending upon various factors such as the duration of the activity, thepatient's fitness level, the time of day, a level of fatigue, anenvironmental temperature, etc. A commensurate heart rate is one that iswithin expected ranges or values for the person's effort, and forfactors inherent to the patient and the environment.

Returning to FIG. 9 , the determined heart rate may be compared to therange(s)/value(s) identified as commensurate with the kinetic indices(920) at a given time point. If the actual heart rate of the patient iswithin the expected/commensurate range or value associated with thekinetic or metabolic indices at the time point, or is within a specifiedproximity of a particular range or value, no action may be taken, andthe method may involve continuing to analyze the patient's cardiac andkinetic signals or metabolic signals. On the other hand, if the heartrate is outside the expected value or range of values for the kinetic ormetabolic indices for that time point, then the heart rate is notcommensurate with the kinetic signal of the patient, and a therapy maybe provided to the patient by applying one of an electrical, thermal,mechanical or chemical signal to a vagus nerve of the patient (930) oradministering to the patient (e.g., intravenously, through mucosae) adrug with cholinergic or anti-cholinergic or adrenergic actions,depending on the case or situation. In one embodiment, the method maycomprise applying the signal to a main trunk of a vagus nerve of thepatient, and in another embodiment, the signal may be applied to acardiac branch of a vagus nerve.

In one embodiment, the heart rate of the patient may be higher than avalue commensurate with the activity level or kinetic indices of thepatient. In this case, the patient is having relative tachycardia. Wherethis is the case, as previously noted, vagus nerve stimulation may beapplied to one or more of a right cardiac branch, left cardiac branch,or right main trunk of the patient's vagus nerve to reduce the patient'sheart rate to a rate that is commensurate with the activity level.Embodiments of the disclosure may be used to treat epileptic seizuresassociated with tachycardia, and other medical conditions associatedwith tachycardia given the patient's activity level. Therapies (e.g.,electrical, chemical, mechanical, thermal) delivered to a patient viathe vagus nerves may be employed for tachyarrythmias, angina pectoris orpain in regions innervated by a vagus nerve.

In another embodiment, the patient's heart rate may be lower than avalue commensurate with the patient's activity level or kinetic indices,that is, the patient is having relative or absolute bradycardia. Highfrequency (>>300 Hz) electrical pulses may be applied to the left orright vagus nerves (e.g., a main trunk of the right and/or left vagusnerves or to their cardiac branches) to block propagation oftransmission of nerve impulses through their fibers. High-frequency VNSmay be applied to block impulses traveling to the heart to abateneurogenic, cardiogenic or iatrogenic bradycardia, or to minimize thecumulative effects on the heart's conduction system and myocardium ofepileptic seizures, especially in status epilepticus. Selective blockageof impulses traveling through a vagus nerve to the heart may beaccomplished with electrical stimulation to treat adverse cardiaceffects associated with disorders such as epilepsy, depression, diabetesor obesity. By blocking vagus nerve conduction to the heart, when thepatient's heart rate is incommensurate with the activity level orkinetic indices, a therapy may be provided to revert the change in heartrate (whether the change involves bradycardia or tachycardia). In oneembodiment, an electrical signal generator may be used to apply a firsttherapy signal to a vagus nerve of the patient, and an electrical signalgenerator (which may be the same or a different electrical signalgenerator) may apply a vagus nerve conduction blocking electrical signalto a vagus nerve (e.g., a cardiac branch of the vagus nerve) to blockcardiac effects that would result from the first electrical signal,absent the vagus nerve conduction blocking electrical signal.

Referring again to FIG. 9 , the method may comprise determining thepatient's heart rate in response the therapy to determine whether theheart rate has been restored to a rate that is with commensurate withthe patient's activity level/kinetic index (940). If not, then thetherapy (e.g., VNS to reduce or increase heart rate to an appropriatevalue) may be continued, with or without parameter modification, orre-initiated after a delay period or confirmation period.

If the heart rate has returned to a range/value commensurate with theactivity level of the patient, the method may, in some embodiments,further involve determining whether or not an adverse event has occurred(950). Adverse events may include, without limitation, side effects suchas voice alteration, pain, difficulty breathing or other respiratoryeffects, adverse cardiac effects such as bradycardia (following adetermination of relative tachycardia in step 920), tachycardia(following a determination of bradycardia in step 920), and alterationin blood pressure or gastro-intestinal activity.

If an adverse event has occurred, the method may involve changing one ormore stimulation parameters to eliminate, reduce or ameliorate theadverse event (955). If no adverse event has occurred, the method maycomprise continuing to apply a signal the vagus nerve until apredetermined signal application duration has been reached (960), atwhich time the signal application may be stopped (970). The method mayfurther comprise determining, after the therapy has been stopped, if thepatient's heart rate remains incommensurate with the patient's activitylevel or type (980), in which case the signal application may be resumedor other appropriate action may be taken (e.g., local or remote alarmsor alerts, notification of caregivers/healthcare providers, etc.). Ifthe heart rate has returned to a value that is commensurate orappropriate for the patient's activity level, the signal application maybe discontinued (990).

FIG. 10 is a flow diagram of a method of treating a patient to withepilepsy by providing closed-loop vagus nerve stimulation to treatrelative tachycardia or relative bradycardia by restoring the patient'sheart rate to a rate that is commensurate with the activity type orlevel of the patient (e.g., as determined from a kinetic signal from asensing element such as a triaxial accelerometer or by measuring oxygenconsumption). In one embodiment, the method comprises identifyinginstances of relative tachycardia or relative bradycardia and respondingwith negative or positive chronotropic actions to restore the heart rateto a level commensurate with the patient's activity type or level.

In one embodiment, the method involves determining a heart rate and anactivity type or level for the patient (1010). The patient's heart ratemay be determined from an acquired cardiac signal or from stored data.The activity level or type of the patient may be determined from one ormore sensor or from stored data. Sensors may include, for example,accelerometers, positional sensors, GPS devices coupled to a clock,postural sensors, and metabolic sensors. Sensor data may be subject toconventional signal processing, and may in addition be adapted ormodified as a function of age, gender, body mass index, fitness level ortime of day or other indices of the patient's condition or environment.

The patient's activity type or level may then be used to determine oneor more heart rate ranges or values that are commensurate with theactivity type or level (1020). In some embodiments, heart rate rangesmay be established for particular levels or types of activity (e.g.,running, walking), that may be adaptively adjusted depending uponvarious factors such as the duration of the activity, the patient'sfitness level, the time of day, a level of fatigue, an environmentaltemperature, etc. A commensurate heart rate is one that is withinexpected ranges or values for the person's effort, and for factorsinherent to the patient and the environment.

If the heart rate is commensurate with the activity level, in oneembodiment no action may be taken, and the method may involve continuingto analyze the patient's cardiac and activity. On the other hand, if theheart rate is outside the identified value or range of valuesappropriate for the patient's activity type or level then the heart rateis not commensurate with the kinetic signal of the patient. Where thisis the case, the method may further comprise determining whether thepatient is experiencing relative tachycardia or is experiencing relativebradycardia (1030, 1040).

Where the heart rate of the patient is higher than a value commensuratewith the activity level or type, the patient is experiencing relativetachycardia (1030), and the method may comprise initiating a negativechronotropic action (1035) to slow the heart rate to a rate that iscommensurate with the activity level or type. In one embodiment, thismay involve applying stimulation to one or more of a left or right mainvagal trunk or cardiac branch of the patient. In other embodiments, themethod may comprise providing a drug to enhance the parasympathetic toneof the patient. In still other embodiments, the method may comprisereducing the patient's sympathetic tone, such as by applyinghigh-frequency stimulation to a sympathetic nerve trunk or ganglion oradministering an anti-cholinergic drug. Negative chronotropic actionsmay be used to treat epileptic seizures associated with tachycardia, andother medical conditions associated with relative tachycardia given thepatient's activity level.

Where the heart rate of the patient is lower than a value commensuratewith the activity level or type, the patient is experiencing relativebradycardia (1040), and the method may comprise initiating a positivechronotropic action (1045) to increase the heart rate to a rate that iscommensurate with the activity level or type. In one embodiment, thismay involve applying high-frequency (>>300 Hz) electrical stimulation toone or more of a left or right main vagal trunk or cardiac branch of thepatient to reduce the transmission of intrinsic vagus nerve actionpotentials in at least some vagal fibers. In other embodiments, themethod may comprise providing a drug to reduce the parasympathetic toneof the patient. In still other embodiments, the method may compriseincreasing the patient's sympathetic tone, such as by applyingelectrical signals to a sympathetic nerve trunk or ganglion or byadministering a sympatho-mimetic drug. Positive chronotropic actions maybe used to treat epileptic seizures associated with bradycardia, andother medical conditions associated with relative bradycardia given thepatient's activity level.

The method may further comprise, after initiating the negative orpositive chronotropic action, determining whether the patient's heartrate has been restored to a rate that is with commensurate with thepatient's activity level/kinetic index (1050). If not, then the therapy(e.g., VNS to reduce or increase heart rate to an appropriate value) maybe continued, with or without parameter modification, or re-initiatedafter a delay period or confirmation period.

If the heart rate has returned to a range/value commensurate with theactivity level of the patient, the method may, in some embodiments,further involve determining whether or not an adverse event has occurred(1060). Adverse events may include, without limitation, side effectssuch as voice alteration, pain, difficulty breathing or otherrespiratory effects, adverse cardiac effects such as bradycardia(following a determination of relative tachycardia in step 1030), ortachycardia (following a determination of bradycardia in step 1040), andalteration in blood pressure or gastric activity.

If an adverse event has occurred, the method may involve changing one ormore stimulation parameters to eliminate, reduce or ameliorate theadverse event (1070). If no adverse event has occurred, the method maycomprise continuing to stimulate the vagus nerve (or a chemical, thermalor mechanical therapy) until a predetermined stimulation duration hasbeen reached (1075), at which time the stimulation may be stopped(1080). The method may further comprise determining, after the therapyhas been stopped, if the patient's heart rate remains incommensuratewith the patient's activity level or type (1090), in which case thestimulation may be resumed or other appropriate action may be taken(e.g., local or remote alarms or alerts, notification ofcaregivers/healthcare providers, use of other forms of therapy, etc.).If the heart rate has returned to a value that is commensurate orappropriate for the patient's activity level, the stimulation may bediscontinued (1095).

Additional embodiments consistent with the foregoing description andfigures may be made. Non-limiting examples of some such embodiments areprovided in the numbered paragraphs below.

-   -   100. A method of controlling a heart rate of an epilepsy patient        comprising:    -   sensing at least one of a kinetic signal and a metabolic signal        of the patient;    -   analyzing the at least one of a kinetic and a metabolic signal        to determine at least one of a kinetic index and a metabolic        index;    -   receiving a cardiac signal of the patient;    -   analyzing the cardiac signal to determine the patient's heart        rate;    -   determining if the patient's heart rate is commensurate with the        at least one of a kinetic index and a metabolic index; and    -   applying an electrical signal to a vagus nerve of the patient        based on a determination that the patient's heart rate is not        commensurate with the at least one of a kinetic signal and a        metabolic signal of the patient.    -   101. The method of numbered paragraph 100, wherein determining        at least one of a kinetic index and a metabolic index comprises        determining at least one of an activity level or an activity        type of the patient based on the at least one of a kinetic index        and a metabolic index, and wherein determining if the patient's        heart rate is commensurate with the at least one of a kinetic        index and a metabolic index of the patient comprises determining        if the heart rate is commensurate with the at least one of an        activity level or an activity type.    -   102. The method of numbered paragraph 101, wherein determining        if the patient's heart rate is commensurate with the at least        one of a kinetic index and a metabolic index comprises        determining if the patient's heart rate is above or below a rate        that is commensurate with the one or more of a kinetic index and        a metabolic index.    -   103. A method of treating a patient having epilepsy comprising    -   sensing at least one body signal of the patient;    -   determining whether or not the patient is having or has had an        epileptic seizure based on the at least one body signal;    -   sensing a cardiac signal of the patient;    -   determining whether or not the seizure is associated with a        change in the patient's cardiac signal;    -   applying a first therapy to a vagus nerve of the patient based        on a determination that the patient is having or has had an        epileptic seizure that is not associated with a change in the        patient's cardiac signal, wherein the first therapy is selected        from an electrical, chemical, mechanical, or thermal signal; and    -   applying a second therapy to a vagus nerve of the patient based        on a determination that the patient is having or has had an        epileptic seizure associated with a change in the patient's        cardiac signal, wherein the second therapy is selected from an        electrical, chemical, mechanical (e.g., pressure) or thermal        signal.    -   104. The method of numbered paragraph 103, further comprising        applying a third therapy to a vagus nerve of the patient based a        determination that the patient is not having or has not had an        epileptic seizure, wherein the third therapy is selected from an        electrical, chemical, mechanical or thermal signal.    -   105. A method of treating a patient having epilepsy comprising:    -   coupling a first set of electrodes to a main trunk of the left        vagus nerve of the patient;    -   coupling a second set of electrodes to a main trunk of the right        vagus nerve of the patient; providing an electrical signal        generator coupled to the first electrode set and the second        electrode set; receiving at least one body data stream;    -   analyzing the at least one body data stream using a seizure        detection algorithm to determine whether or not the patient is        having and/or has had an epileptic seizure;    -   applying a first electrical signal from the electrical signal        generator to the main trunk of the left vagus nerve, based on a        determination that the patient is having and/or has had an        epileptic seizure without a heart rate change; and    -   applying a second electrical signal from the electrical signal        generator to the main trunk of the right vagus nerve, based on a        determination that the patient is having or has had an epileptic        seizure with a heart rate change.    -   106. A method of treating a patient having epilepsy comprising:    -   receiving at least one body data stream;    -   analyzing the at least one body data stream using a seizure        detection algorithm to detect whether or not the patient has had        an epileptic seizure;    -   receiving a cardiac signal of the patient;    -   analyzing the cardiac signal to determine a first cardiac        feature;    -   applying a first electrical signal to a vagus nerve of the        patient, based on a determination that the patient has not had        an epileptic seizure characterized by a change in the first        cardiac feature, wherein the first electrical signal is not a        vagus nerve conduction blocking electrical signal; and    -   applying a second electrical signal to a vagus nerve of the        patient, based on a determination that the patient has had an        epileptic seizure characterized by a change in the cardiac        feature, wherein the second electrical signal is a pulsed        electrical signal that blocks action potential conduction in the        vagus nerve.    -   107. A method of treating a patient having epilepsy comprising:    -   receiving at least one body data stream;    -   analyzing the at least one body data stream using a seizure        detection algorithm to detect whether or not the patient has had        an epileptic seizure;    -   receiving a cardiac signal of the patient;    -   analyzing the cardiac signal to determine a first cardiac        feature;    -   applying a first electrical signal to a vagus nerve of the        patient, based on a determination that the patient has not had        an epileptic seizure characterized by a change in the first        cardiac feature, wherein the first electrical signal is a pulsed        electrical signal that blocks action potential conduction in the        vagus nerve; and    -   applying a second electrical signal to a vagus nerve of the        patient, based on a determination that the patient has had an        epileptic seizure characterized by a change in the cardiac        feature, wherein the second electrical signal is not a vagus        nerve conduction blocking electrical signal.

In FIG. 11 , a graph of heart rate versus time is shown, according toone embodiment. A first graph 1100 includes a y-axis 1102 whichrepresents heart rate where the heart rate goes from a zero value to anNth value (e.g., 200 heart beats, etc.). Further, the first graph 1100includes an x-axis 1104 which represents time from 1 minute to Nthminutes (and/or 0.001 seconds to Nth seconds). In this example, a firstheart rate versus time line 1106 for the patient is shown. In thisexample, the patient's heart rate goes from 80 heart beats per minute to118 heart beats per minute with a first rise 1108A and a first run 1108Bduring a first event 1108C. In addition, the patient's heart rate goesfrom 70 heart beats per minute to 122 heart beats per minute during asecond event 1108D which has a first percentage change 1110 associatedwith the second event 1108D. Further, the patient's heart rate goes from70 beats per minute to 113 beats per minute during an nth event 1108Ewhich surpasses a first threshold amount 1112, and/or a second thresholdamount 1114, and/or an Nth threshold amount 1116. In one example, onlythe Nth threshold amount 1116 needs to be reached to trigger a therapyand/or an alert. In another example, only the second threshold amount1114 needs to be reached to trigger a therapy and/or an alert.

In another example, only the first threshold 1112 needs to be reached totrigger a therapy and/or an alert. In another example, both the Nththreshold 1116 and the second threshold 1114 need to reached to triggera therapy and/or an alert. In another example, all of the Nth threshold1116, the second threshold 1114 and the first threshold 1112 need toreached to trigger a therapy and/or an alert. In one example, only theNth threshold amount 1116 needs to be reached during a specific timeperiod to trigger a therapy and/or an alert. In another example, onlythe second threshold amount 1114 needs to be reached during a specifictime period to trigger a therapy and/or an alert. In another example,only the first threshold 1112 needs to be reached during a specific timeperiod to trigger a therapy and/or an alert. In another example, boththe Nth threshold 1116 and the second threshold 1114 need to reachedduring a specific time period to trigger a therapy and/or an alert. Inanother example, all of the Nth threshold 1116, the second threshold1114 and the first threshold 1112 need to reached during a specific timeperiod to trigger a therapy and/or an alert. In these examples, one ormore triggering events may occur based on a determination of the riseand run of a change in heart rate, a percentage change in heart rate, athreshold amount being reached or exceeded (or within any percentage ofthe threshold), and/or any combination thereof. A triggering event mayinitiate one or more actions to increase and/or decrease the patient'sheart rate. For example, if the patient's heart rate is increasing whichdetermines the triggering event, then the system, device, and/or methodmay initiate one or more actions to decrease the heart rate of thepatient to help reduce, dampen, eliminate, and/or buffer the increase inthe patient's heart rate. Further, the system, device, and/or method mayoscillate between decreasing the patient's heart rate and increasing thepatient's heart rate depending on any changes to the patient's heartrate. For example, the system, device, and/or method may initiate one ormore actions to decrease a patient's heart rate based on the patient'sheart rate going from 80 heart beats per minute to 130 heart beats perminute which results in the patient's heart rate falling from 130 heartbeats per minute to 65 heart beats per minute in a first time period.Based on the change in the heart rate from 130 heart beats per minute to65 heart beats per minute in the first time period, the system, device,and/or method may initiate one or more actions to increase the patient'sheart rate and/or stabilize the patient's heart rate. In anotherexample, the system, method, and/or device may stop and/or modify anyinitiated action based on one or more feedback signals. In addition, oneor more warnings may be transmitted to the patient, a caregiver, adoctor, a medical professional, and/or logged.

In FIG. 12 , another graph of heart rate versus time is shown, accordingto one embodiment. A second graph 1200 illustrating a second heart rateversus time line 1202 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 120 heartbeats per minute which creates a first system alert event 1204 (e.g.,A1). Further, the system, device, and/or method initiates a firsttherapy 1206 (e.g., X1) based on the first system alert event 1204. Inaddition, a second system alert event 1208 (e.g., A2) occurs and asecond therapy 1210 (e.g., X2) is initiated based on the second systemalert event 1208. In addition, a third system alert event 1212 (e.g.,A3) occurs and a third therapy (e.g., X3) 1214 is initiated based on thethird system alert event 1212 (e.g., A3). In addition, a fourth systemalert event 1216 (e.g., A4) occurs and a fourth therapy 1218 (e.g., X4)is initiated based on the fourth system alert event 1216 (e.g., A3).Further, a fifth therapy 1220 (e.g., X5) is initiated based on theeffects of the fourth therapy 1218 (e.g., X4). In addition, a fifthsystem alert event 1222 (e.g., A5) occurs and a sixth therapy (e.g., X6)1224 is initiated based on the fifth system alert event 1222 (e.g., A5).In addition, a sixth system alert event 1226 (e.g., A6) occurs and aseventh therapy (e.g., X7) 1228 is initiated based on the sixth systemalert event 1226 (e.g., A6). In addition, a seventh system alert event1230 (e.g., A7) occurs and an eighth therapy (e.g., X8) 1232 isinitiated based on the seventh system alert event 1230 (e.g., A7). Inaddition, a first stop stimulation event 1234 (e.g., B1) occurs whichturns off all therapies and/or system alerts may occur when the heartrate returns to the approximate starting heart rate and/or a targetvalue. In these examples shown with FIG. 12 , a rise over run heart ratecalculation was completed to determine the one or more system alerts.However, it should be noted that any calculation (e.g., % increase, %decrease, etc. can be utilized). Further, all systems alerts and/ortherapies may occur as independent events and/or examples. For example,the seventh system alert may be the first system alert in a specificexample. In other words, no other events and/or therapies occurredbefore the seventh system alert. Therefore, the seventh system alertbecomes the first system alert. In addition, one or more warnings may betransmitted to the patient, a caregiver, a doctor, a medicalprofessional, and/or logged. In addition, there may be up to an Nthalerts, an Nth stop stimulation (and/or therapy) event, and an Nththerapy in any of the examples disclosed in this document.

In FIG. 13 , another graph of heart rate versus time is shown, accordingto one embodiment. A third graph 1300 illustrating a third heart rateversus time line 1302 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 116 heartbeats per minute which creates a first system alert event 1304 (e.g.,A1). Further, the system, device, and/or method initiates a firsttherapy 1306 (e.g., X1) based on the first system alert event 1304. Inaddition, a first stop stimulation event 1308 (e.g., B1) occurs whichturns off all therapies and/or system alerts occurs when the heart ratereturns to the approximate starting heart rate and/or a target value.Further, the patient's heart rate goes from 80 heart beats per minute to123 heart beats per minute which creates a second system alert event1310 (e.g., A2). Further, the system, device, and/or method initiates asecond therapy 1312 (e.g., X2) based on the second system alert event1310. In addition, a second stop stimulation event 1314 (e.g., B2)occurs which turns off all therapies and/or system alerts occurs whenthe heart rate returns to the approximate starting heart rate and/or atarget value. In these examples shown with FIG. 13 , a percentage changein heart rate calculation was completed to determine the one or moresystem alerts. However, it should be noted that any calculation (e.g.,rise over run, etc. can be utilized). Further, all systems alerts and/ortherapies may occur as independent events and/or examples. For example,the second system alert may be the first system alert in a specificexample. In other words, no other events and/or therapies occurredbefore the second system alert. Therefore, the second system alertbecomes the first system alert. In addition, one or more warnings may betransmitted to the patient, a caregiver, a doctor, a medicalprofessional, and/or logged.

In FIG. 14 , another graph of heart rate versus time is shown, accordingto one embodiment. A fourth graph 1400 illustrating a fourth heart rateversus time line 1402 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 120 heartbeats per minute which creates a first system alert event 1404 (e.g.,A1) because the 120 heart beats per minutes meets or exceeds a firstthreshold value 1416 (e.g., 115 heart beats per minute). In thisexample, a second system alert event 1406 (e.g., A2) is created becausethe heart beats of the patient meets or exceeds the first thresholdvalue 1416 (e.g., 115 heart beats per minute). Further, the system,device, and/or method initiates a first therapy 1408 (e.g., X1) based onthe first system alert event 1404 and the second system alert event 1406occurring. The first system alert event 1404 and the second system alertevent 1406 may be time dependent. For example, the first system alertevent 1404 and the second system alert event 1406 may have to occurwithin a first time period for the initiation of the first therapy 1408.In another example, the first system alert event 1404 and the secondsystem alert event 1406 may not be time dependent. Further, a thirdsystem alert event 1410 (e.g., A3) is created because the heart beats ofthe patient meets or exceeds (and/or within a specific rate of thethreshold—in this example within 5 percent—heart rate is 110) the firstthreshold value 1416 (e.g., 115 heart beats per minute). Further, thesystem, device, and/or method initiates a second therapy 1412 (e.g., X2)based on the first system alert event 1404, the second system alertevent 1406, and/or the third system event occurring. It should be notedthat the second therapy 1412 has a time delay factor utilized with thesecond therapy 1412. In another example, no time delay is utilized. Inaddition, one or more time delays can be used with any therapy, anywarning, and/or any alert in this document. The first system alert event1404, the second system alert event 1406, and the third system alertevent 1410 may be time dependent. For example, the first system alertevent 1404, the second system alert event 1406, and the third systemalert event 1410 may have to occur within a first time period for theinitiation of the second therapy 1412. In another example, the firstsystem alert event 1404, the second system alert event 1406, and thethird system alert event 1410 may not be time dependent. Further, afirst stop stimulation event 1414 (e.g., B1) occurs which turns off alltherapies and/or system alerts occurs when the heart rate returns to theapproximate starting heart rate and/or a target value. Further, allsystems alerts and/or therapies may occur as independent events and/orexamples. For example, the third system alert may be the first systemalert in a specific example. In other words, no other events and/ortherapies occurred before the third system alert. Therefore, the thirdsystem alert becomes the first system alert. In addition, one or morewarnings may be transmitted to the patient, a caregiver, a doctor, amedical professional, and/or logged.

In FIG. 15 , another graph of heart rate versus time is shown, accordingto one embodiment. A fifth graph 1500 illustrating a fifth heart rateversus time line 1502 for the patient is shown. In this example, thepatient's heart rate goes from 80 heart beats per minute to 40 heartbeats per minute which creates a first system alert event 1504 (e.g.,A1) because the 40 heart beats per minutes meets or exceeds a firstthreshold value 1520 (e.g., 50 heart beats per minute). It should benoted that no alert was generated when the heart rate fell to 52 heartbeats per minute because 52 heart beats per minute is above thethreshold value of 50 heart beats per minute. Further, the system,device, and/or method initiates a first therapy 1506 (e.g., X1) based onthe first system alert event 1504 occurring. Further, the patient'sheart rate goes from 80 heart beats per minute to 50 heart beats perminute which creates a second system alert event 1508 (e.g., A2) becausethe 50 heart beats per minutes meets or exceeds the first thresholdvalue 1520 (e.g., 50 heart beats per minute). Further, the system,device, and/or method initiates a second therapy 1510 (e.g., X2) basedon the second system alert event 1508 occurring. Further, a first stopstimulation event 1512 (e.g., B1) occurs which turns off all therapiesand/or system alerts occurs when the heart rate returns to theapproximate starting heart rate and/or a target value. In addition, thepatient's heart rate goes from 80 heart beats per minute to 45 heartbeats per minute which creates an nth system alert event 1514 (e.g., A3)because the 45 heart beats per minutes meets or exceeds the firstthreshold value 1520 (e.g., 50 heart beats per minute). Further, thesystem, device, and/or method initiates an Nth therapy 1516 (e.g., X3)based on the nth system alert event 1514 occurring. Further, an nth stopstimulation event 1518 (e.g., B2) occurs which turns off all therapiesand/or system alerts occurs when the heart rate returns to theapproximate starting heart rate and/or a target value. Further, allsystems alerts and/or therapies may occur as independent events and/orexamples. For example, nth system alert event 1514 alert may be thefirst system alert in a specific example. In other words, no otherevents and/or therapies occurred before nth system alert event 1514.Therefore, nth system alert event 1514 becomes the first system alert.In addition, one or more warnings may be transmitted to the patient, acaregiver, a doctor, a medical professional, and/or logged.

In regards to FIGS. 11-15 as related to this disclosure, the systems,devices, and/or methods may use a base line heart rate for the patient(e.g., a specific patient Bob, a general patient John Doe with a firsthealth condition, a first age, etc.) over a first time period (e.g. oneweek, one month, one year, etc.), 50 percentile of all measured heartrates, an average of all heart rates, and/or any other method ofdetermine a baseline heart rate. Further, the threshold level may bedetermined based on being the 40 percentile of the baseline, 39percentile of the baseline, 38 percentile of the baseline, . . . , 10percentile of the baseline, . . . , etc. In addition, the thresholdlevel may be determined based on being the 75 percentile of thebaseline, 76 percentile of the baseline, 77 percentile of the baseline,. . . , 90 percentile of the baseline, . . . , 99 percentile of thebaseline, . . . , etc. In one example, the threshold value may be the 75percentile of every recorded heart rate data. In another example, theoscillation does not matter whether the heart rate change is in anincreasing direction or a decreasing direction. In various examples, thesystems, devices, and/or method may reduce an amplitude of change (e.g.,damping the change in heart rate) to enhance system performance and/orto reduce side effects. In addition, the determination of one or moreside effects may initiate a reduction in therapy, a stoppage of therapy,a modification of therapy (e.g., changing a therapy that reduces heartrate to another therapy that increases heart rate), one or morewarnings, and/or one or more logging of data.

In FIG. 16 , a flowchart of a therapy procedure is shown, according toone embodiment. A method 1600 includes obtaining one or more data pointsand/or characteristics relating to heart rate of a patient (step 1602).The method 1600 may also include determining a monitored value based onethe obtained one or more data points and/or characteristics relating tothe heart rate (step 1604). The method 1600 may further compare themonitored value to one or more threshold values (step 1606). The method1600 may via one or more processors (of a medical device(s) and/ormedical device system) determine whether a triggering event has occurred(step 1608). If no triggering event has occurred, then the method 1600moves back to step 1602. If a triggering event has occurred, then themethod 1600 may determine via one or more processors (of a medicaldevice(s) and/or medical device system) whether an action whichincreases heart rate should be implemented (step 1610). If an actionwhich increases heart rate should be implemented, then the method 1600may increase a sympathetic tone via one or more actions and/or decreasea parasympathetic tone via one or more actions and/or implement anotheraction which increases heart rate (step 1612). After the implements ofone or more actions, the method 1600 returns to step 1602. If an actionwhich increases heart rate should not be implemented, then the method1600 may determine via one or more processors (of a medical device(s)and/or medical device system) whether an action which decreases heartrate should be implemented (step 1614). If an action which decreasesheart rate should be implemented, then the method 1600 may decrease asympathetic tone via one or more actions and/or increase aparasympathetic tone via one or more actions and/or implement anotheraction which decreases heart rate (step 1616). After the implements ofone or more actions, the method 1600 returns to step 1602.

In one embodiment, a system for treating a medical condition in apatient includes: a sensor for sensing at least one body data stream; aheart rate unit capable of determining a heart rate of the patient basedon the at least one body data stream; and a logic unit configured viaone or more processors to compare a monitored value which is determinedbased on one or more data points relating to the heart rate to one ormore threshold values, the logic unit further configured to determine atriggering event based on the comparison. Further, the one or moreprocessors may initiate one or more actions to change the heart rate ofthe patient based on the determination of the triggering event.

In another example, the system includes at least one electrode coupledto a vagus nerve of the patient and a programmable electrical signalgenerator. In another example, the one or more processors may increase asympathetic tone to increase the heart rate of the patient. In anotherexample, the one or more processors may decrease a parasympathetic toneto increase the heart rate of the patient. In another example, the oneor more processors may decrease a sympathetic tone to decrease the heartrate of the patient. In another example, the one or more processors mayincrease a parasympathetic tone to decrease the heart rate of thepatient. In another example, the system includes a seizure detectionunit which analyzes the at least one body data stream to determine anepileptic seizure status. In another example, the system includes atleast one electrode coupled to a vagus nerve of the patient and aprogrammable electrical signal generator. Further, the one or moreprocessors may apply an electrical signal to the vagus nerve of thepatient based on a determination that a seizure is characterized by adecrease in the heart rate of the patient where the electrical signal isapplied to block action potential conduction on the vagus nerve.

In another embodiment, a system for treating a medical condition in apatient, includes: a sensor for sensing at least one body data stream;at least one electrode coupled to a vagus nerve of the patient; aprogrammable electrical signal generator; a heart rate unit capable ofdetermining a heart rate of the patient based on the at least one bodydata stream; and a logic unit configured via one or more processors tocompare a monitored value which is determined based on one or more datapoints relating to the heart rate to one or more threshold values, thelogic unit further configured to determine a triggering event based onthe comparison. Further, the one or more processors may initiate one ormore actions to change the heart rate of the patient based on thedetermination of the triggering event.

In another example, the one or more processors may increase asympathetic tone to increase the heart rate of the patient based on afirst triggering event. Further, the one or more processors may decreasea sympathetic tone to decrease the heart rate of the patient based on asecond triggering event. Further, the one or more processors maydecrease a parasympathetic tone to increase the heart rate of thepatient based on a third triggering event. Further, the one or moreprocessors may increase a parasympathetic tone to decrease the heartrate of the patient based on a fourth triggering event.

In another example, the one or more processors may increase thesympathetic tone to increase the heart rate of the patient based on asecond triggering event. Further, the one or more processors mayincrease the sympathetic tone to increase the heart rate of the patientbased on a third triggering event. Further, the one or more processorsincrease the sympathetic tone to increase the heart rate of the patientbased on an nth triggering event.

In another example, the one or more processors decrease a sympathetictone to decrease the heart rate of the patient based on a firsttriggering event. Further, the one or more processors decrease thesympathetic tone to decrease the heart rate of the patient based on asecond triggering event. Further, the one or more processors maydecrease the sympathetic tone to decrease the heart rate of the patientbased on a third triggering event. In addition, the one or moreprocessors decrease the sympathetic tone to decrease the heart rate ofthe patient based on an nth triggering event.

Cardio-protection in epilepsy is a rapidly growing field of vitalimportance. In this disclosure, systems, devices, and/or method ofprotecting the heart from standstill or fatal arhythmias are disclosed.Further in this disclosure, systems, devices, and/or methods ofautomated detections, warnings, reportings, treatments, controls and/orany combination thereof of ictal and peri-ictal chronotropic instabilityare shown.

In FIG. 17 , a graph shows monotonic increase and decrease in heartrate. In FIG. 17 , a first triggering event, a first warning event,and/or a first therapy event 1702 are shown. Further, a secondtriggering event 1704, a second warning event, and/or a second therapyevent 1704 are shown. In addition, an Nth triggering event, an Nthwarning event, and/or an Nth therapy event 1706 are shown. In FIG. 18 ,the heart rate of the patient increases which is followed by a decreasein heart rate, then an increase heart rate and a final decrease in heartrate. In this example, the first drop in heart rate crossed downwardlythe detection threshold which would have temporarily disabled thewarning system and the delivery of the therapy. While the first peak wasnot temporally correlated with paroxysmal activity on any of theintra-cranial electrodes used in this patient, it is likely that thefirst increase in heart rate was caused by epileptic discharges from abrain site that was not being investigated. In this example, the x-axisis time in hours and the y-axis is heart beats per minute. In thisexample, an electrographic onset in the brain 1810 is shown and anelectrographic termination in the brain 1812 is shown.

In FIG. 19 , a change in ictal heart rate is shown. In this example, thedrop in heart rate during the seizure, is even more prominent that theone depicted in FIGS. 17-18 , as it is below the inter-ictal baseline.It should be noted that the oscillations in heart rate during thepost-ictal period are indicative of cardiac instability. In thisexample, a seizure onset point 1910 and a seizure termination point 1912are shown.

In FIG. 20 , large amplitude tachycardia cycles occurringquasi-periodically after termination of paroxysmal activity recordedwith intra-cranial electrodes. While the mechanisms responsible forthese oscillations are unknown, the probability that they are epilepticin nature cannot be excluded, since electrographic and imaging data usedto guide intra-cranial electrode placement pointed to the existence ofonly one epileptogenic site.

In FIG. 21 , small amplitude continuous quasi-periodic oscillationspreceding and following a seizure recorded with intra-cranial electrodes(same patient as FIG. 20 ). In various embodiments, ictal and peri-ictalcardiac instability are shown. The mechanisms leading to SUDEP have notbeen elucidated, in part due to the inability to record data during thecritical events that culminate in cardiac fibrillation or in standstill(or in respiratory arrest). In this example, a first triggering event, afirst warning event, and/or a first therapy event 2102 are shown.Further, an Nth triggering event, an Nth warning event, and/or an Nththerapy event 2104 are shown.

The data obtained in intractable epileptics undergoing epilepsy surgeryevaluation not only supports a cardiac mechanism (of course, not at theexclusion of catastrophic respiratory failure) but more specificallypoints to chronotropic instability as backdrop against which, lethalarrhythmias or cardiac standstill may ensue. Moreover, the instabilityis not restricted to the ictal period but, in certain cases, precedesand/or follows it for several minutes. FIGS. 17-21 illustrate thespectrum of instability in intractable epileptics. This phenomenon isreferred herein to as Ictal and Pre-Ictal Chronotropic Instability.

The challenges that for accurate quantification and delivery ofefficacious therapies, ictal chronotropic instability poses, wereaddressed and strategies to manage them are outlined. Here, theattention is focused on Ictal and Pre-Ictal Chronotropic Instability, amore prolonged and serious pathological phenomenon in intractableepileptics and on the vital issues of cardio-protection.

The aim of this disclosure is to contingently and adaptively dampenbased on the slope, amplitude, duration and “direction” (positive ornegative chronotropic and its magnitude relative to an adaptivebaseline/reference heart rate) the heart oscillations present before,during or after epileptic seizures.

While several embodiments may be envisioned, on embodiment (forefficacy, practicality and cost-effectiveness) is to electricallystimulate/activate the trunk or a branch of the right vagus nerve in thecase of elevations in heart (to reduce the heart rate, when there aremore than 2 consecutive oscillations/cycles or 1 that is large andprolonged. The intensity and duration of stimulation as well as otherparameters are determined by the slope, amplitude and duration of theoscillations, while ensuring adequate blood perfusion to all organs. Inthe case of negative chronotropic effects (decreases in heart rate) thetrunk or a branch of the right vagus nerve may be “blocked” usingcertain electrical stimulation techniques or through cooling; the effectof this intervention is to increase heart rate.

In one embodiment, the “height” of the oscillation is the only featureconsidered. While obviously important, this embodiment does not takeinto consideration a possibly more important feature: the rate at whichthe oscillation occurs: the consequences of waiting to intervene untilan oscillation reaches a certain height (e.g., 120 bpm) are different ifit takes, 30 seconds for the heart rate to reach the value than if ittakes 2 seconds to reach the value. Estimating the rate of change of theheart rate, provides life-saving information. Another aspect is theinter-maxima or inter-minima interval between oscillations. Having heartrate oscillation occur every 2-3 seconds is much more serious than every1-2 hours. In one example, one benefit may be that the window to act islengthen which can save lives. In one embodiment, a system for treatinga medical condition in a patient includes: a sensor for sensing at leastone body data stream; a heart rate unit which determines a heart rateand a heart rate oscillation of the patient based on the at least onebody data stream; and a logic unit which compares via one or moreprocessors a monitored value which is determined based on one or moredata points relating to the heart rate and to the heart rate oscillationto a threshold value, the logic unit determines a triggering event basedon the comparison where the one or more processors initiate one or moreactions to change the heart rate of the patient based on thedetermination of the triggering event.

In another example, the system includes at least one electrode coupledto a vagus nerve of the patient and a programmable electrical signalgenerator. Further, the one or more processors may increase asympathetic tone to increase the heart rate of the patient. In anotherexample, the one or more processors may decrease a parasympathetic toneto increase the heart rate of the patient. In another example, the oneor more processors may decrease a sympathetic tone to decrease the heartrate of the patient. Further, the one or more processors may increase aparasympathetic tone to decrease the heart rate of the patient. Inaddition, the system may include a seizure detection unit which analyzesthe at least one body data stream to determine an epileptic seizurestatus. The system may include at least one electrode coupled to a vagusnerve of the patient and a programmable electrical signal generatorwhere the one or more processors apply an electrical signal to the vagusnerve of the patient based on a determination that a seizure ischaracterized by a decrease in the heart rate of the patient and wherethe electrical signal is applied to block action potential conduction onthe vagus nerve. In addition, the heart unit may determine aninter-maxima interval and an inter-minima interval between a firstoscillation and a second oscillation. Further, the logic unit maycompare the inter-maxima interval and the inter-minima interval to aninterval threshold. In addition, the one or more processors may initiateone or more actions based on the interval threshold being reached.

The particular embodiments disclosed above are illustrative only as thedisclosure may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown other than as describedin the claims below. It is, therefore, evident that the particularembodiments disclosed above may be altered or modified and all suchvariations are considered within the scope and spirit of the disclosure.Accordingly, the protection sought herein is as set forth in the claimsbelow. In addition, all examples, embodiments, and/or elements may becombined in any manner that are disclosed in this document. In otherwords, an element from a first example (paragraph) [0088]) can becombined with any other element, such as, a second element from an Nthexample (paragraph [0163]). For brevity, all these examples are notwritten out but are part of this document.

Identification of changes in brain state (whether physiologic orpathologic) has traditionally been accomplished through analysis ofelectrical brain signals and behavioral observation. Continuous (e.g.,round-the-clock) automated monitoring of changes in brain state imposescertain limitations on the utilization of these traditional methods, dueto the difficulties inherent to automated ambulatory video, the largeamount of data produced per unit time, and the excessive demands onhuman and technical resources required to maintain an acceptablesignal/noise for electrical signals recorded from the scalp.Additionally, scalp signals have poor temporo-spatial resolution, acharacteristic which results in both low sensitivity and specificity ofstate-of-brain detection changes.

Implanted sensors or electrodes beneath the scalp but above the outerskull table or intra-cranial (epidural, subdural or depth) have beenused to overcome the limitations of scalp recordings. However, althoughthe quality of recordings (especially for intracranial electrodes) ismuch better (e.g., typically has a higher S/N) than that from scalpelectrodes, the quality is still limited and there are risks (e.g.,infection, bleeding, brain damage) associated with these devices, not tomention cost and scarcity of neurosurgeons to perform this type ofprocedures.

While electrical brain signals and behavioral observation may provideinformation for classification of brain states, this task can beaccomplished more efficiently, and/or more cost-effectively throughmonitoring of other biological signals under control of the brain suchthose generated by the heart, muscle, skin, eyes, tympanic membranetemperature, and body posture/movement, since they may not requiresurgery, or if surgery is required for implantation, the procedures aremuch shorter, simpler, and cheaper that those required for recording ofbrain signals and there is no shortage of human resources.

Certain highly valuable neurological signals (e.g., cognitive) fordetection, quantification, and classification of state changes mayobtained non-invasively and can be used in this disclosure.

In one aspect, the present disclosure is directed to differentiatingbetween generalized or convulsive epileptic and non-epileptic seizures.In another aspect, extra-cerebral signals may be also used to detect anddistinguish partial epileptic from partial non-epileptic seizures.

Extra-cerebral signals (e.g., EKG, body movements, respirations, etc.)denote herein body signals that may be recorded/obtained without placingsensors or electrodes on the head (e.g., scalp or under it) or insidethe head/skull (e.g., subdural electrodes/sensors, depth orintra-cerebral electrodes/sensors) and are directly or indirectly undercontrol of the central or peripheral nervous system. Cognitive signalssuch as attention/responsiveness, language, memory among others, whiledirectly generated by the brain are considered extra-cerebral herein,since they may be recorded/obtained without resorting tosensors/electrodes placed on/inside the head. Extra-cerebral signalsprovide valuable and reliable information about the state of the brainsince they are either generated by the brain or under its control.

Aspects of extra-cerebral signals such as magnitude, rate of change(including return to non-seizure levels), and morphology (e.g.,waveform), vary depending on whether the event affecting theextra-cerebral signal(s) is epileptic or non-epileptic. The presentdisclosure discloses methods and apparatus for using such signals todistinguish between these seizure types. For example, althoughmovements, cardiac and respiratory rate increase during both epilepticand non-epileptic seizures, the type, magnitude and duration of changes(much different and greater with epileptic seizures) can be used,according to the present disclosure, for accurate classification of theseizure as epileptic or non-epileptic.

Although in many embodiments discussed herein, at least oneextra-cerebral signal may be used for differentiation of non-epilepticseizures from epileptic ones, nothing in this disclosure precludes theuse of cerebral signals for said purpose.

These extra-cerebral (e.g., autonomic, neurologic, etc.) signals can beused individually or in combination to monitor continuously the brainand generate a state-of the-system/organ report, in real-time for thedetection, quantification, classification, validation, control andlogging of physiologic or pathologic state changes. This approach takesadvantage of the inherent and finely tuned dynamical coupling amongthese systems. For instance, changes in brain state/activity may resultin changes in heart activity, muscle activity, and skin properties.

Herein, Applicant describes a method, systems, and devices that may: a)detect in real-time pre-specified changes in brain state; b) quantifytheir duration, intensity, extent of spread, and time of occurrence; c)classify their type (e.g., epileptic vs. non-epileptic seizures;primarily vs. secondarily generalized seizures; generalized vs. partialseizures; complex vs., simple partial seizures; d) use as a basis forwarning and control/therapy, and/or e) save this information to memoryfor future retrieval for optimization of detection, quantification andclassification of state changes and assessment and optimization oftherapeutic (e.g., control) efficacy. Non-epileptic movements in thisdisclosure refer to those resembling movements seen during tonic-clonicseizures but which are not caused by those abnormal electrical activitythat characterizes epileptic seizures.

In embodiments where extra-cerebral data is the basis for a detection,cerebral signals, such as EEG/ECoG, evoked potentials, field potentials,or single unit activity, among others, may be used for validation,confirmation, or the like of the extra-cerebral detections ordeterminations made from extra-cerebral data.

The extra-cerebral epileptic and/or non-epileptic event detectiondisclosed herein provides a comprehensive, cost-effective, valuablealternative to systems of epileptic or non-epileptic event detectionbased on brain electrical signals such as EEG. To date, noextra-cerebral systems for detection of both epileptic and non-epilepticseizures have been developed or commercialized. Extra-cerebral epilepticand non-epileptic event detection may make use of one or more signals ofautonomic, neurologic, endocrine, metabolic, gastro-intestinal, and/ordermal origin and of tissue/organ stress markers, such as thosepresented in Table 1.

Extra-cerebral detection of state changes takes advantage of the factthat certain brain structures directly or indirectly influenceautonomic, endocrine, gastro-intestinal, dermal and metabolic functionsand that certain abnormal states (e.g. seizures) stress the body tissuesand result in the elevation of certain compounds or molecules (e.g.,stress markers) that may be used to detect, quantify and verify theoccurrence of said abnormal state.

It has been established that seizures in humans originating from orspreading to central autonomic structures induce changes in heart rate,among other cardio-vascular indices, and also in respiratory activity.It should be stated that seizure-induced heart rate or respiratoryincreases (which are far more frequent than heart rate or respiratoryrate decreases) are not primarily the result of increased motor activityor of metabolic changes, but are instead largely a neurogenicphenomenon.

In the present disclosure, a highly robust, efficient and reliablesystem is provided for detecting, quantifying and/or classifyingepileptic and/or non-epileptic seizures based upon at least oneextra-cerebral signal and, if desired, using this information to providewarnings, or notification, of the type of seizure event (epileptic ornon-epileptic) detected. In some embodiments, systems of the presentdisclosure may take appropriate therapeutic interventions that reflect(for efficacy and safety purposes) their etiologic and patho-physiologicdifferences. Systems of the present disclosure are suitable forlong-term implantable or external devices, and may provide reliable andaccurate indications of seizure events for a wide variety of epilepsyand/or non-epilepsy patients.

Extra-Cerebral Multimodal Signals (Table 1) Autonomic

-   -   Cardiac: EKG, PKG, Echocardiography, Apexcardiography (ApKG),        Intra-cardiac pressure, Cardiac blood flow, cardiac        thermography; from which can be derived, e.g., heart rate (HR),        change of HR, rate of change of HR, heart rate variability        (HRV), change of HRV, rate of change of HRV, HRV vs. HR. Also,        blood pressure, heart sounds, heart rhythm, heartbeat wave        morphology, heartbeat complex morphology, and thoracic wall        deflection.    -   Vascular: Arterial Pressure, Arterial and venous blood wave        pressure morphology; Arterial and venous blood flow velocity,        arterial and venous blood flow sounds, arterial and venous        thermography    -   Respiratory: Frequency, tidal volume, minute volume, respiratory        wave morphology, respiratory sounds, end-tidal CO₂, Intercostal        EMG, Diaphragmatic EMG, chest wall and abdominal wall motion,        from which can be derived, e.g., respiration rate (RR), change        of RR, rate of change of RR. Also, arterial gas concentrations,        including oxygen saturation, as well as blood pH can be        considered respiratory signals.    -   Other autonomic: Skin resistance, skin temperature, skin blood        flow, sweat gland activity, body temperature, organ temperature.    -   Concentrations of catecholamines (and their metabolites) and        acetylcholine or acetylcholinesterase activity in blood, saliva        and other body fluids concentrations and its rate of change.

Neurologic

-   -   Cognitive/behavioral: Level of consciousness, attention,        reaction time, memory, visuo-spatial, language, reasoning,        judgment, mathematical calculations, auditory, and/or visual        discrimination.    -   Kinetic: Direction, speed/acceleration, trajectory (1D to 3D),        pattern, and quality of movements, force of contraction, body        posture, body orientation/position, body part        orientation/position in reference to each other and to imaginary        axes, muscle tone, agonist-to-antagonist muscle tone relation,        from which can be derived, e.g., information about gait,        posture, normal or abnormal head, ocular, trunk, pelvis, and        limb movements and falls.    -   Vocalizations: Formed, unformed, rate of production/unit time,        pitch, loudness, duration.

Endocrine

-   -   Prolactin, luteinizing hormone, follicle stimulation hormone,        growth hormone, ACTH, cortisol, vasopressin, beta-endorphin,        beta, lipotropin-, corticotropin-releasing factor (CRF).

Tissue Stress Markers

-   -   CK, lactic acid, troponin, neuron-specific enolase, reactive        oxygen and nitrogen species including but not limited to iso-        and neuro-prostanes and nitrite/nitrate ratio, glutathione,        glutathione disulfide and glutathione peroxidase activity,        citrulline, protein carbonyls, thiobarbituric acid, the heat        shock protein family, catecholamines, lactic acid,        N-acetylaspartate, and metabolites of any of the foregoing.

Metabolic

-   -   Arterial pH and gases, lactate/pyruvate ratio, electrolytes,        glucose, oxygen consumption.

Certain body signals may fall within more than one class. For example,pH is listed in Table 1 as both an autonomic signal, since it is underrespiratory control, and a metabolic signal, since it is also influencedby metabolic by-products.

Generally, when the term “reference value” is used herein withoutfurther qualification, it refers to a value of an index determined fromautonomic, neurologic, endocrine, metabolic, or stress marker data andderived from an interictal, ictal or postictal period of an epileptic orof a non-epileptic seizure. The evolution of non-epileptic seizures atlong temporal scales (e.g., days to years) behaves similarly to that ofepileptic seizures, having “interictal” periods when no abnormalactivity occurs, “ictal” periods when the abnormal activity is visible(e.g., “loss of consciousness and generalized abnormal motor activity)and “postictal” periods (e.g., the abnormal movements cease but thepatient remains “unresponsive”). Reference values or ranges thereof forany of the autonomic, neurologic, endocrine, metabolic or stress markerfeatures may be dependent upon the patient's level of consciousness(e.g., wakefulness), level of physical (e.g., exercise) or cognitiveactivity (e.g., attentive), time of day (e.g., circadian), or seizurehistory (e.g., mean or median time between seizures, seizure severity,etc., over short-term or long-term time periods) and are thusnon-stationary. Although reference values for a certain feature in acertain patient state and/or time are most directly comparable tocorresponding signals in the same patient state and/or time of day, theymay be comparable to corresponding signals from other states, times, orboth.

A reference value may be a mean, median, or another statisticalindicator of the central tendency of a data series or of itsdistribution (e.g. probability distribution or density function). Thereference value may be a threshold that is useful—depending upon theunderlying index or feature being considered—for distinguishing betweenan epileptic (ictal) state and a non-ictal state, and also fordistinguishing a convulsive/generalized epileptic from aconvulsive/generalized non-epileptic state. Body movements of severalbody parts occur during both convulsive/generalized epileptic andnon-epileptic seizures but differences in velocity, force direction andnumber of planes which the movement traverses, may be used todistinguish epileptic from non-epileptic seizures.

The reference value may be from a data series taken from the samepatient on whom the present methods may be performed, or a plurality ofdata series taken from each member of a population of patients. If thereference value is derived from the patient's own data, it is desirablefor the patient to have an epileptic and/or a non-epileptic seizurehistory, in order to identify activity that is indicative of anepileptic and/or non-epileptic seizure, and thereby to obtain data thatmay be used as reference value for comparison purposes. The referencevalue may be empirical in origin or derived from accepted wisdom in thefield.

The various embodiments disclosed by parent U.S. patent application Nos.13/098,262 and 12/896,525 may be also used to distinguish epilepticgeneralized from psychogenic non-epileptic generalized seizures whosekinetic activity, but not patho-physiology, resembles that of epilepticseizures.

An extra-cerebral signal approach relying on multiple body signals suchas kinetic, autonomic and metabolic signals, and that may be performedin ambulatory patients (unlike video-EEG monitoring, the current “goldstandard” that requires hospitalization for several days) is ideallysuited for classifying seizures as either epileptic or non-epileptic,given the high sensitivity and specificity inherent to a multimodal“extra-cerebral” signal approach according to the disclosure describedherein. Embodiments of the present disclosure may be implemented insmall portable devices, which would provide a cost-effective solution(no hospital admission would be necessary) to a pressing medical need.

The following are a few examples of features of epileptic and/ornon-epileptic seizures, one or more of which may be used to distinguishbetween epileptic generalized/convulsive seizures and non-epilepticgeneralized/convulsive seizures: a) The intensity of non-epilepticmovements, unlike that of epileptic movements, waxes and wanes(crescendo-decrescendo pattern) throughout the event; b) Non-epilepticmovements, unlike epileptic movements, are multi-directional ormulti-planar, said changes in direction or plane occurring rapidly andoften in a random sequence. For example, vertical movements may give wayto horizontal movements, and these in turn to oblique or rotary orflapping movements; c) Body joints movements in non-epileptic seizures,unlike in epileptic seizures, are incoherent or disorganized: e.g.,while the right upper extremity is moving in the vertical plane at acertain speed and with certain amplitude and phase, the direction,speed, phase and amplitude of movement of the left upper extremity atthe same time may be different; d) in non-epileptic seizures, unlike inepileptic seizures, co-activation of agonist and antagonist musclegroups is rarely seen: Co-activation of the abdominal and paraspinalmuscles during an epileptic generalized tonic-clonic seizure keeps thetorso straight while the sole activation of paraspinal muscles, a commonobservable in non-epileptic generalized seizures, manifests as an archedback (opisthotonus); unopposed activation of neck, trunk, hip flexorsresults in the so-called “fetal position”, also a common occurrence innon-epileptic seizures; e) Involvement (in the form of movements) ofcertain body parts is commonly found in non-epileptic seizures whilethey are rarely if ever seen in epileptic generalized seizures; pelvicthrust, pelvic gyrations, and other pelvic movements are nearlypathognomic of non-epileptic seizures; f) Metabolic (lactic) acidosisoccurs with epileptic generalized tonic-clonic seizures and not withnon-epileptic generalized seizures; g) oxygen desaturation and carbondioxide retention are seen in epileptic convulsive but not innon-epileptic convulsive seizures.

Although not limited to the following, an exemplary system capable ofimplementing embodiments of the present disclosure is described below.

Turning now to FIG. 22 , a stylized medical device system is depicted.The medical device system comprises a medical device 2300 and at leastone sensor 2312.

In some embodiments, the medical device 2300 may be implantable, whilein other embodiments, such as that shown in FIG. 22 ; the medical device2300 may be completely external to the body of the patient. In stillother embodiments, the present disclosure may comprise systems with someimplantable portions and some external portions.

The sensor 2312 may be implanted in the patient's body, worn external tothe patient's body, or positioned in proximity to but not in contactwith the patient's body. The sensor 2312 may be configured to receivecardiac activity data, body movement data, responsiveness data,awareness data, or other data from the patient's body.

FIG. 22 depicts the medical device 2300 being in wired communication2311 with the at least one sensor 2312. In other embodiments (notshown), the medical device 2300 may be in wireless communication withthe at least one sensor 2312.

Turning now to FIG. 23 , a block diagram depiction of a systemcomprising a medical device 2300 is provided, in accordance with oneillustrative embodiment of the present disclosure. In some embodiments,the medical device 2300 may be implantable, while in other embodimentsthe medical device 2300 may be completely external to the body of thepatient. In still other embodiments, the medical device may include bothimplanted and non-implanted portions. FIG. 23 illustrates variouscomponents, units and/or modules that perform functions discussed morefully below. It will be appreciated that these components and units ormodules may be equivalently described using similar terms, and the useof particular terms herein is not intended to exclude embodimentsinvolving different components performing the same function, or whichmay be described using different but similar terms.

The medical device 2300 may comprise a controller 2310 capable ofcontrolling various aspects of the operation of the medical device 2300.The controller 2310 is capable of receiving internal data or externaldata and is capable of affecting substantially all functions of themedical device 2300.

The controller 2310 may comprise various components, such as a processor2315, a memory 2317, etc. The processor 2315 may comprise one or moremicrocontrollers, microprocessors, etc., capable of performing variousexecutions of software components. The memory 2317 may comprise variousmemory portions where a number of types of data (e.g., internal data,external data instructions, software codes, status data, diagnosticdata, etc.) may be stored. In one embodiment, the memory 2317 may beconfigured to store at least one reference value of an autonomicactivity, a neurologic activity, a metabolic activity, an endocrineactivity, or a stress marker activity. The memory 2317 may comprise oneor more of random access memory (RAM), dynamic random access memory(DRAM), electrically erasable programmable read-only memory (EEPROM),flash memory, etc.

The medical device 2300 may also comprise a power supply 2330. The powersupply 2330 may comprise a battery, voltage regulators, capacitors,etc., to provide power for the operation of the medical device 2300,including delivering the therapeutic electrical signal. The power supply2330 comprises a power source that in some embodiments may berechargeable. In other embodiments, a non-rechargeable power source maybe used. The power supply 2330 provides power for the operation of themedical device 2300, including electronic operations and the electricalsignal generation and delivery functions. The power supply 2330 maycomprise a lithium/thionyl chloride cell or a lithium/carbonmonofluoride (LiCFx) cell if the medical device 2300 is implantable, ormay comprise conventional watch or 9V batteries for external (i.e.,non-implantable) embodiments. Other battery types known in the art ofmedical devices may also be used.

The medical device 2300 may also comprise a communication unit 2360capable of facilitating communications between the medical device 2300and various devices. In particular, the communication unit 2360 iscapable of providing transmission and reception of electronic signals toand from a monitoring unit 2370, such as a handheld computer or PDA thatcan communicate with the medical device 2300 wirelessly or by cable. Thecommunication unit 2360 may include hardware, software, firmware, or anycombination thereof.

The medical device 2300 may also comprise one or more sensor(s) 2312coupled via sensor lead(s) 2311 to the medical device 2300 (or inwireless communication with the medical device 2300, not shown). Thesensor(s) 2312 are capable of receiving signals related to aphysiological parameter, such as an autonomic signal, a neurologicsignal, a metabolic signal, an endocrine signal, or a stress markersignal, among others, and delivering the signals to the medical device2300. The at least one sensor(s) 2312, in one embodiment, may comprisean accelerometer. The at least one sensor(s) 2312, in anotherembodiment, may comprise an inclinometer. In another embodiment, the atleast one sensor(s) 2312 may comprise an actigraph. One or more of theat least one sensor(s) 2312 may be external structures that may beplaced on the patient's skin, such as over the patient's heart orelsewhere on the patient's torso. The at least one sensor(s) 2312, inone embodiment, may comprise a multimodal signal sensor capable ofdetecting various signals, such as autonomic and neurologic signals.

In one embodiment, the medical device 2300 may comprise a autonomicsignal module 2365 that is capable of collecting autonomic data, e.g.,cardiac data comprising fiducial time markers of each of a plurality ofheart beats, a blood SaO2 value, a blood CO₂ concentration, a blood pHvalue, a body temperature, or an infrared activity of a portion of apatient's body, among others. The autonomic signal module 2365 may alsoprocess or condition the autonomic data. The autonomic data may beprovided by the sensor(s) 2312. The autonomic signal module 2365 may becapable of performing any necessary or suitable amplifying, filtering,and performing analog-to-digital (A/D) conversions to prepare thesignals for downstream processing. The autonomic data module 2365, inone embodiment, may comprise software module(s) that are capable ofperforming various interface functions, filtering functions, etc. Inanother embodiment, the autonomic signal module 2365 may comprisehardware circuitry that is capable of performing these functions. In yetanother embodiment, the autonomic signal module 2365 may comprisehardware, firmware, software and/or any combination thereof. A moredetailed illustration of the autonomic signal module 2365 is provided inFIG. 24A and accompanying description below.

The autonomic signal module 2365 is capable of collecting autonomic dataand providing the collected autonomic data to a detection unit 2385, aclassification unit 2386, or both.

In one embodiment, the medical device 2300 may comprise a neurologicalsignal module 2375 that is capable of collecting neurologic data, e.g.,signals indicative of a motor activity of the patient, such as acrescendo-decrescendo pattern of a motor activity, a force of a motoractivity, a velocity of a motor activity, a multi-directionality of amotor activity, a multi-planarity of a motor activity, a frequency of amotor activity, an incoherence or asymmetry between a first motoractivity and a second motor activity, a lack of coactivation duringcertain motor activity of an agonist muscle group and an antagonistmuscle group, or a pelvic motor activity, among others. (“Lack” and“absence” may be used interchangeably herein). The neurological signalmodule 2375 may also process or condition the neurologic data. Theneurologic data may be provided by the sensor(s) 2312. The neurologicalsignal module 2375 may be capable of performing any necessary orsuitable amplifying, filtering, and performing analog-to-digital (A/D)conversions to prepare the signals for downstream processing. Theneurological signal module 2375, in one embodiment, may comprisesoftware module(s) that are capable of performing various interfacefunctions, filtering functions, etc. In another embodiment, theneurological signal module 2375 may comprise hardware circuitry that iscapable of performing these functions. In yet another embodiment, theneurological signal module 2375 may comprise hardware, firmware,software and/or any combination thereof. Further description of theneurologic signal module 2375 is provided in FIG. 24B and accompanyingdescription below.

The neurological signal module 2375 is capable of collecting neurologicdata and providing the collected neurologic data to a detection unit2385, a classification unit 2386, or both.

In one embodiment, the medical device 2300 may comprise a metabolicsignal module 2376 that is capable of collecting metabolic data, e.g.,signals indicative of a metabolic activity of the patient, such as alactic acid concentration or a potassium concentration, among others.The metabolic signal module 2376 may also process or condition themetabolic data. The metabolic data may be provided by the sensor(s)2312. The metabolic signal module 2376 may be capable of performing anynecessary or suitable amplifying, filtering, and performinganalog-to-digital (A/D) conversions to prepare the signals fordownstream processing. The metabolic signal module 2376, in oneembodiment, may comprise software module(s) that are capable ofperforming various interface functions, filtering functions, etc. Inanother embodiment, the metabolic signal module 2376 may comprisehardware circuitry that is capable of performing these functions. In yetanother embodiment, the metabolic signal module 2376 may comprisehardware, firmware, software and/or any combination thereof. Furtherdescription of the metabolic signal module 2376 is provided in FIG. 24Cand accompanying description below.

The metabolic signal module 2376 is capable of collecting metabolic dataand providing the collected metabolic data to a detection unit 2385, aclassification unit 2386, or both.

In one embodiment, the medical device 2300 may comprise an endocrinesignal module 2378 that is capable of collecting endocrine data, e.g.,signals indicative of an endocrine activity of the patient, such as aprolactin concentration, a luteinizing hormone concentration, afollicle-stimulating hormone (FSH) concentration, a growth hormoneconcentration, an ACTH concentration, a cortisol concentration, avasopressin concentration, a β-endorphin concentration, a β-lipotropinconcentration, or a CRF concentration, among others. The endocrinesignal module 2378 may also process or condition the endocrine data. Theendocrine data may be provided by the sensor(s) 2312. The endocrinesignal module 2378 may be capable of performing any necessary orsuitable amplifying, filtering, and performing analog-to-digital (A/D)conversions to prepare the signals for downstream processing. Theendocrine signal module 2378, in one embodiment, may comprise softwaremodule(s) that are capable of performing various interface functions,filtering functions, etc. In another embodiment, the endocrine signalmodule 2378 may comprise hardware circuitry that is capable ofperforming these functions. In yet another embodiment, the endocrinesignal module 2378 may comprise hardware, firmware, software and/or anycombination thereof. Further description of the endocrine signal module2378 is provided in FIG. 24D and accompanying description below.

The endocrine signal module 2378 is capable of collecting endocrine dataand providing the collected endocrine data to a detection unit 2385, aclassification unit 2386, or both.

In one embodiment, the medical device 2300 may comprise a stress markersignal module 2379 that is capable of collecting stress marker data,e.g., signals indicative of a stress marker activity of the patient,such as a reactive oxygen concentration, a reactive nitrogenconcentration, or a catecholamine concentration, among others. Thestress marker signal module 2379 may also process or condition thestress marker data. The stress marker data may be provided by thesensor(s) 2312. The stress marker signal module 2379 may be capable ofperforming any necessary or suitable amplifying, filtering, andperforming analog-to-digital (A/D) conversions to prepare the signalsfor downstream processing. The stress marker signal module 2379, in oneembodiment, may comprise software module(s) that are capable ofperforming various interface functions, filtering functions, etc. Inanother embodiment, the stress marker signal module 2379 may comprisehardware circuitry that is capable of performing these functions. In yetanother embodiment, the stress marker signal module 2379 may comprisehardware, firmware, software and/or any combination thereof. Furtherdescription of the stress marker signal module 2379 is provided in FIG.24E and accompanying description below.

The stress marker signal module 2379 is capable of collecting stressmarker data and providing the collected stress marker data to adetection unit 2385, a classification unit 2386, or both.

The detection unit 2385 may be capable of detecting a seizure. Thedetection unit 2385 may make use of an autonomic signal provided byautonomic signal module 2365, a neurological signal module 2375, othermodules depicted in FIG. 23 , modules not shown in the figures, or twoor more thereof. The detection unit 2385 can implement one or morealgorithms. The detection unit 2385 may comprise software module(s) thatare capable of performing various interface functions, filteringfunctions, etc. In another embodiment, the detection unit 2385 maycomprise hardware circuitry that is capable of performing thesefunctions. In yet another embodiment, the detection unit 2385 maycomprise hardware, firmware, software and/or any combination thereof.Further description of an exemplary detection unit 2385 is provided inU.S. patent application Nos. 13/098,262 and 12/896,525.

In another embodiment, the medical device 2300 may further comprise atherapy unit. The therapy unit (not shown) may be configured to at leastone of administer a non-epileptic seizure therapy, prevent delivery ofan epilepsy therapy, or warn against delivery of an epilepsy therapy, inresponse to receiving from the detection unit an indication the seizureis non-epileptic. In one embodiment, the medical device 2300 may furthercomprise a notification unit. The notification unit (not shown) may beconfigured to notify at least one of the patient, a caregiver, or amedical professional that the seizure is non-epileptic, based upon anindication that the seizure is non-epileptic. In one embodiment, themedical device 2300 may further comprise a logging unit. The loggingunit (not shown) may be configured to log at least one of the date ofoccurrence of the seizure, the time of occurrence of the seizure, or theseverity of the seizure.

In addition to components of the medical device 2300 described above, amedical device system may comprise a storage unit to store an indicationof at least one of seizure or an increased risk of a seizure. Thestorage unit may be the memory 2317 of the medical device 2300, anotherstorage unit of the medical device 2300, or an external database, suchas a local database unit 2355 or a remote database unit 2350. Themedical device 2300 may communicate the indication via thecommunications unit 2360. Alternatively or in addition to an externaldatabase, the medical device 2300 may be adapted to communicate theindication to at least one of a patient, a caregiver, or a healthcareprovider.

In various embodiments, one or more of the units or modules describedabove may be located in a monitoring unit 2370 or a remote device 2392,with communications between that unit or module and a unit or modulelocated in the medical device 2300 taking place via communication unit2360. For example, in one embodiment, one or more of the autonomicsignal module 2365, the neurologic signal module 2375, or the detectionunit 2385 may be external to the medical device 2300, e.g., in amonitoring unit 2370. Locating one or more of the autonomic signalmodule 2365, the neurologic signal module 2375, or the detection unit2385 outside the medical device 2300 may be advantageous if thecalculation(s) is/are computationally intensive, in order to reduceenergy expenditure and heat generation in the medical device 2300 or toexpedite calculation.

The monitoring unit 2370 may be a device that is capable of transmittingand receiving data to and from the medical device 2300. In oneembodiment, the monitoring unit 2370 may be a computer system capable ofexecuting a data-acquisition program. The monitoring unit 2370 may becontrolled by a healthcare provider, such as a physician, at a basestation in, for example, a doctor's office. In alternative embodiments,the monitoring unit 2370 may be controlled by a patient in a systemproviding less interactive communication with the medical device 2300than another monitoring unit 2370 controlled by a healthcare provider.Whether controlled by the patient or by a healthcare provider, themonitoring unit 2370 may be a computer, preferably a handheld computeror PDA, but may alternatively comprise any other device that is capableof electronic communications and programming, e.g., hand-held computersystem, a PC computer system, a laptop computer system, a server, apersonal digital assistant (PDA), an Apple-based computer system, acellular telephone, etc. The monitoring unit 2370 may download variousparameters and program software into the medical device 2300 forprogramming the operation of the medical device, and may also receiveand upload various status conditions and other data from the medicaldevice 2300. Communications between the monitoring unit 2370 and thecommunication unit 2360 in the medical device 2300 may occur via awireless or other type of communication, represented generally by line2377 in FIG. 23 . This may occur using, e.g., wand 155 (FIG. 1A) tocommunicate by RF energy with an implantable signal generator 110.Alternatively, the wand may be omitted in some systems, e.g., systems inwhich the MD 2300 is non-implantable, or implantable systems in whichmonitoring unit 2370 and MD 2300 operate in the MICS bandwidths.

In one embodiment, the monitoring unit 2370 may comprise a localdatabase unit 2355. Optionally or alternatively, the monitoring unit2370 may also be coupled to a database unit 2350, which may be separatefrom monitoring unit 2370 (e.g., a centralized database wirelesslylinked to a handheld monitoring unit 2370). The database unit 2350and/or the local database unit 2355 are capable of storing variouspatient data. These data may comprise patient parameter data acquiredfrom a patient's body, therapy parameter data, seizure severity data,and/or therapeutic efficacy data. The database unit 2350 and/or thelocal database unit 2355 may comprise data for a plurality of patients,and may be organized and stored in a variety of manners, such as in dateformat, severity of disease format, etc. The database unit 2350 and/orthe local database unit 2355 may be relational databases in oneembodiment. A physician may perform various patient management functions(e.g., programming parameters for a responsive therapy and/or settingreferences for one or more detection parameters) using the monitoringunit 2370, which may include obtaining and/or analyzing data from themedical device 2300 and/or data from the database unit 2350 and/or thelocal database unit 2355. The database unit 2350 and/or the localdatabase unit 2355 may store various patient data.

One or more of the blocks illustrated in the block diagram of themedical device 2300 in FIG. 23 may comprise hardware units, softwareunits, firmware units, or any combination thereof. Additionally, one ormore blocks illustrated in FIG. 23 may be combined with other blocks,which may represent circuit hardware units, software algorithms, etc.Additionally, any number of the circuitry or software units associatedwith the various blocks illustrated in FIG. 23 may be combined into aprogrammable device, such as a field programmable gate array, an ASICdevice, etc.

Turning to FIG. 24A, an autonomic signal module 2365 is shown in moredetail. The autonomic signal module 2365 can comprise a cardiovascularsignal unit 2412 capable of providing at least one cardiovascularsignal. Alternatively or in addition, the autonomic signal module 2365can comprise a respiratory signal unit 2414 capable of providing atleast one respiratory signal. Alternatively or in addition, theautonomic signal module 2365 can comprise a blood parameter signal unit2423 capable of providing at least one blood parameter signal (e.g.,blood glucose, blood pH, blood gas, SaO2 value, CO2 concentration,etc.). Alternatively or in addition, the autonomic signal module 2365can comprise a temperature signal unit 2416 capable of providing atleast one temperature signal. Alternatively or in addition, theautonomic signal module 2365 can comprise an optic signal unit 2418capable of providing at least one optic signal. Alternatively or inaddition, the autonomic signal module 2365 can comprise a chemicalsignal unit 2420 capable of providing at least one body chemical signal.Alternatively or in addition, the autonomic signal module 2365 cancomprise one or more other autonomic signal unit(s) 2424, such as a skinresistance signal unit or an infrared activity unit configured toprovide at least one signal relating to an infrared activity of aportion of a patient's body, among others.

The autonomic signal module 2365 can also comprise an autonomic signalprocessing unit 2430. The autonomic signal processing unit 2430 canperform any filtering, noise reduction, amplification, or otherappropriate processing of the data received by the signal units2412-2424 desired prior to calculation of the autonomic signal.

The autonomic signal module 2365 can also comprise an autonomic signalcalculation unit 2440. The autonomic signal calculation unit 2440 cancalculate an autonomic signal from the data passed by the autonomicsignal processing unit 2430. A calculated autonomic signal herein refersto any signal derivable from the provided signals, with or withoutprocessing by the autonomic signal processing unit 2430.

More description regarding the autonomic signal module 2365 may be foundin U.S. patent application Nos. 13/098,262 and 12/896,525.

Turning to FIG. 24B, an exemplary embodiment of a neurologic signalmodule 2375 is shown. The neurologic signal module 2375 can comprise atleast one of a neuro-electrical signal unit 24012 capable of providingat least one neuro-electrical signal; a neuro-chemical signal unit 24014capable of providing at least one neuro-chemical signal; aneuro-electrochemical signal unit 24016 capable of providing at leastone neuro-electrochemical signal; a kinetic signal unit 24018 capable ofproviding at least one kinetic signal; or a cognitive signal unit 24020capable of providing at least one cognitive signal. The cognitive signalunit 24020 may be a component of a remote device.

In one embodiment, the cognitive signal unit comprises at least one of acognitive aptitude determination unit 24020 a capable of processing atleast one cognitive aptitude indication; an attention aptitudedetermination unit 24020 b capable of processing at least one attentionaptitude indication; a memory aptitude determination unit 24020 ccapable of processing at least one memory indication; a languageaptitude determination unit 24020 d capable of processing at least onelanguage indication; a visual/spatial aptitude determination unit 24020e capable of processing at least one visual/spatial indication; one ormore other neurologic factor determination unit(s) 24020 g; or aresponsiveness determination unit 24020 h.

The neurologic signal module 2375 can also comprise a neurologic signalprocessing unit 24030. The neurologic signal processing unit 24030 canperform any filtering, noise reduction, amplification, or otherappropriate processing of the data received by the signal units24012-24020 desired prior to calculation of the neurologic signal.

The neurologic signal module 2375 can also comprise a neurologic signalcalculation unit 24040. The neurologic signal calculation unit 24040 cancalculate a neurologic signal from the data passed by the neurologicsignal processing unit 24030. A calculated neurologic signal hereinrefers to any signal derivable from the provided signals.

For example, the neurologic signal calculation unit 24040 may calculatea motor activity signal, such as a signal relating to acrescendo-decrescendo pattern of a motor activity, a force of a motoractivity, a velocity of a motor activity, a multi-directionality of amotor activity, a multi-planarity of a motor activity, a frequency of amotor activity, an incoherence or asymmetry between a first motoractivity and a second motor activity, a lack of coactivation duringmotor activity of an agonist muscle group and an antagonist musclegroup, or a pelvic motor activity.

Other motor activity signal(s) that may be calculated from relevant datainclude those relating to the body's (or of a portion thereof such asthe head, eyes, an arm, or a leg) acceleration; direction; position;smoothness, amplitude, force of movements and number of movements perunit time, and whether there are extraneous or abnormal bodyoscillations during resting conditions or movement. The data sourcesfrom which the signal may be calculated include electromyography, amechanogram, an accelerometer, an actigraph, an inclinometer, or avideo/optical signal, as received by kinetic capability determinationunit 24018, and, optionally, further processed by neurologic dataprocessing unit 24030.

More description regarding the neurologic signal module 2375 may befound in U.S. patent application Nos. 13/098,262 and 12/896,525.

Turning to FIG. 24C, an exemplary embodiment of a metabolic signalmodule 2376 is shown. The metabolic signal module 2376 can comprise atleast one of a lactic acid signal unit 24110 capable of providing atleast one signal relating to lactic acid content in the patient's bloodand/or a tissue; or a potassium signal unit 24112 capable of providingat least one signal relating to a potassium content in the patient'sblood or tissue.

The metabolic signal module 2376 can also comprise a metabolic signalprocessing unit 24130. The metabolic signal processing unit 24130 canperform any filtering, noise reduction, amplification, or otherappropriate processing of the data received by the signal units24110-24112 desired prior to calculation of the metabolic signal.

The metabolic signal module 2376 can also comprise a metabolic signalcalculation unit 24140. The metabolic signal calculation unit 24140 cancalculate a metabolic signal from the data passed by the metabolicsignal processing unit 24130. A calculated metabolic signal hereinrefers to any signal derivable from the provided signals.

For example, the metabolic signal calculation unit 24140 may calculate alactic acid signal, such as may be determinable from signals yielded bya blood lactic acid sensor, as received by the lactic acid signal unit24110 and, optionally, further processed by metabolic data processingunit 24130.

For another example, the metabolic signal calculation unit 24140 maycalculate a potassium signal, such as the potassium ion content of thepatient's blood. The signal may be received by potassium signal unit24112, and, optionally, further processed by metabolic data processingunit 24130.

Turning to FIG. 24D, an exemplary embodiment of an endocrine signalmodule 2378 is shown. The endocrine signal module 2378 can comprise atleast one of a prolactin signal unit 24210 capable of providing at leastone signal relating to prolactin content in the patient's blood; aluteinizing hormone signal unit 24211 capable of providing at least onesignal relating to luteinizing hormone content in the patient's blood;an FSH signal unit 24212 capable of providing at least one signalrelating to FSH content in the patient's blood; a growth hormone signalunit 24213 capable of providing at least one signal relating to growthhormone content in the patient's blood; an ACTH signal unit 24214capable of providing at least one signal relating to ACTH content in thepatient's blood; a cortisol signal unit 24215 capable of providing atleast one signal relating to cortisol content in the patient's blood; avasopressin signal unit 24216 capable of providing at least one signalrelating to vasopressin content in the patient's blood; a β-endorphinsignal unit 24217 capable of providing at least one signal relating toβ-endorphin content in the patient's blood; a β-lipotropin signal unit24218 capable of providing at least one signal relating to β-lipotropincontent in the patient's blood; a CRF signal unit 24219 capable ofproviding at least one signal relating to CRF content in the patient'sblood; or another endocrine signal unit 24220 capable of providing atleast one signal relating to another endocrine property.

The endocrine signal module 2378 can also comprise an endocrine signalprocessing unit 24230. The endocrine signal processing unit 24230 canperform any filtering, noise reduction, amplification, or otherappropriate processing of the data received by the signal units24210-24220 desired prior to calculation of the endocrine signal.

The endocrine signal module 2378 can also comprise an endocrine signalcalculation unit 24240. The endocrine signal calculation unit 24240 cancalculate an endocrine signal from the data passed by the endocrinesignal processing unit 24230. A calculated endocrine signal hereinrefers to any signal derivable from the provided signals.

For example, the endocrine signal calculation unit 24240 may calculate acortisol signal, such as may be determinable from signals yielded by ablood cortisol sensor, as received by the cortisol signal unit 24215and, optionally, further processed by endocrine data processing unit24230.

Turning to FIG. 24E, an exemplary embodiment of a stress marker signalmodule 2379 is shown. The stress marker signal module 2379 can compriseat least one of a reactive oxygen signal unit 24310 capable of providingat least one signal relating to the content of at least one reactiveoxygen species in the patient's blood or a tissue; a reactive nitrogensignal unit 24311 capable of providing at least one signal relating tothe content of at least one reactive nitrogen species in the patient'sblood or a tissue; a catecholamine signal unit 24312 capable ofproviding at least one signal relating to catecholamine content in thepatient's blood or a tissue; or another stress marker signal unit 24313capable of providing at least one signal relating to another stressmarker.

The stress marker signal module 2379 can also comprise a stress markersignal processing unit 24330. The stress marker signal processing unit24330 can perform any filtering, noise reduction, amplification, orother appropriate processing of the data received by the signal units24310-24313 desired prior to calculation of the stress marker signal.

The stress marker signal module 2379 can also comprise a stress markersignal calculation unit 24340. The stress marker signal calculation unit24340 can calculate a stress marker signal from the data passed by thestress marker signal processing unit 24330. A calculated stress markersignal herein refers to any signal derivable from the provided signals.

For example, the stress marker signal calculation unit 24340 maycalculate a reactive oxygen signal, such as may be determinable fromsignals yielded by a sensor of peroxide and/or superoxide ions in thepatient's blood, as may be received by the reactive oxygen signal unit24310 and, optionally, further processed by stress marker dataprocessing unit 24330.

From any one or more signal(s) calculated by any calculation unitdepicted in FIGS. 24A-24E, one or more autonomic activities, neurologicactivities, metabolic activities, endocrine activities, or stress markeractivities may be determined. Turning to FIG. 24F, a block diagram ofclassification unit 2386 is depicted. The classification unit 2386comprises a calculated signal receiving unit 24610 capable of receivingdata indicative of a calculated signal from one or more of the autonomicsignal module 2365, the neurologic signal module 2375, the metabolicsignal module 2376, the endocrine signal module 2378, the stress markersignal module 2379, or a memory 2317 storing prior outputs of such amodule, and seizure classification unit 24620 capable of determiningfrom the received data whether a seizure is epileptic, non-epileptic,another type of behavior or motor changes (e.g., behavior changesarising from dissociation or motor changes arising from Huntington'schorea or paroxysmal choreo-athetosis, or unclassifiable. The seizureclassification unit 24620 may implement any appropriate algorithm(s) forclassifying a seizure from at least one autonomic signal, neurologicsignal, metabolic signal, endocrine signal, or stress marker signal.

The classification unit 2386 may be configured to classify the seizureas a non-epileptic seizure, based on at least one of the following: anautonomic activity being not indicative of an epileptic seizure, aneurologic activity being not indicative of an epileptic seizure, ametabolic activity being not indicative of an epileptic seizure, anendocrine activity being not indicative of an epileptic seizure, or astress marker activity being not indicative of an epileptic seizure.

In the embodiment shown in FIG. 24F, the classification unit 2386 mayfurther comprise a seizure quantification unit 24630 capable ofquantifying from the received data one or more quantifiablecharacteristics of one or both of an epileptic seizure and anon-epileptic seizure. Exemplary quantifiable characteristics include,but are not limited to, event severity, event duration, duration ofstages of the event, or values and/or ranges thereof of one or more bodysignals (e.g., a blood chemical value, a lactic acid content, aparameter of a motor activity, etc.), among others.

The classification unit 2386 may send the output of the seizureclassification unit 24620 to one or more other units or modules of themedical device 2300 and/or one or more external units. The one or moreother modules may then store the output, report the output to thepatient, a physician, and/or a caregiver; warn the patient or acaregiver that the event under consideration is non-epileptic, etc.

The medical device system of one embodiment of the present disclosureprovides for software module(s) that are capable of acquiring, storing,and processing various forms of data, such as patient data/parameters(e.g., physiological data, side-effects data, heart rate data, breathingrate data, brain-activity parameters, disease progression or regressiondata, quality of life data, etc.) and therapy parameter data. Therapyparameters in the case of epileptic seizures may include, but are notlimited to, electrical signal parameters (e.g., frequency, pulse width,wave shape, polarity, geometry of electrical fields, on-time, off-time,etc.) that define therapeutic electrical signals delivered by themedical device in response to the detection of the seizure, medicationtype, dose, or other parameters, and/or any other therapeutic treatmentparameter.

In one embodiment, the medical device 2300 or an external unit 2370 mayalso be capable of detecting a manual input from the patient. The manualinput may include a magnetic signal input, a tap input, a button, dial,or switch input, a touchscreen input, a wireless data input to themedical device 2300, etc. The manual input may be used to allow captureof the patient's subjective assessment of his or her epileptic events.For example, the medical device 2300 may comprise one or more physicalor virtual (e.g., touchscreen-implemented) buttons accessible to thepatient's fingers or a caregiver's, through which the patient orcaregiver may indicate he or she is having an epileptic event or is nothaving an epileptic event. Alternatively or in addition, the manualinput may be used to gauge the patient's responsiveness. Turning now toFIG. 25 , a flowchart depiction of a method according to oneillustrative embodiment of the present disclosure is presented. Aseizure in a patient may be detected at 2510 using any appropriatetechnique(s), such as those described above. In one embodiment,detecting at 2510 may comprise observing at least one abnormal motoractivity of the patient (i.e., motor activity associated with anepileptic seizure).

At least one signal indicative of an activity of the patient may bereceived at 2520. The at least one signal may be any one or more of thefollowing: an autonomic signal indicative of an autonomic activity ofthe patient, a neurologic signal indicative of a neurologic activity ofthe patient, a metabolic signal indicative of a metabolic activity ofthe patient, an endocrine signal indicative of an endocrine activity ofthe patient, or a stress marker signal indicative of a stress marker ofthe patient, among others.

Based on the at least one received signal, the seizure may be classifiedat 2530 as a non-epileptic seizure based on at least one of thefollowing: the autonomic activity being an autonomic activity notindicative of an epileptic seizure, the neurologic activity being aneurologic activity not indicative of an epileptic seizure, themetabolic activity being a metabolic activity not indicative of anepileptic seizure, the endocrine activity being an endocrine activitynot indicative of an epileptic seizure, or the stress marker activitybeing a stress marker activity not indicative of an epileptic seizure.

In a particular example, the autonomic activity not indicative of anepileptic generalized/convulsive seizure may be at least one of: a lackof a decrease of SaO2 value of the patient's blood after the onset of ageneralized motor activity, relative to a reference SaO2 value, a lackof an increase in CO2 concentration of the patient's blood after theonset of a generalized motor activity, relative to a reference CO2concentration, a lack of a decrease in a pH value of the patient's bloodafter the onset of a generalized motor activity essentially unchangedrelative to a reference pH value, a lack of an increase in the patient'sbody temperature after the onset of a generalized motor activity duringthe seizure, relative to a reference temperature value, a lack of changein the patient's cardiac activity after the onset of a generalized motoractivity, relative to a reference cardiac activity value, or a lack ofan increase in an infrared activity of a portion of the patient's bodyafter the onset of a generalized motor activity, relative to a referenceinfrared activity.

In an even more particular example, the autonomic activity notindicative of an epileptic seizure may be a lack of a decrease in a pHvalue of the patient's blood after the onset of a generalized motoractivity essentially unchanged relative to a reference pH value.

In another particular example, the neurologic activity not indicative ofan epileptic seizure is at least one of: a recurringcrescendo-decrescendo pattern of a motor activity of the patient, aforce of a motor activity of the patient, a range of motion of a motoractivity of the patient, a velocity of a motor activity of the patient,a multi-directionality of a motor activity of the patient, amulti-planarity of a motor activity of the patient, a frequency of amotor activity of the patient, an incoherence between a first motoractivity and a second motor activity of the patient, a lack ofcoactivation during motor activity of an agonist muscle group and anantagonist muscle group of the patient, or a pelvic motor activity ofthe patient that is the most prominent body movement of the patient.

Body movement is a type of motor activity. However, some motor activitymay be associated with a lack of body movement; e.g., a tonic phase of aseizure is associated with a marked increase in muscle tone but is alsoassociated with substantially no movement of the patient's body.

“Crescendo-decrescendo” is used herein to refer to a pattern ofincreasing amplitude of a motor activity, followed by a decreasingamplitude of the motor activity. The crescendo-decrescendo pattern maybe recurrent and periodic or aperiodic.

In this context, coherence or being in phase refers to any feature ofmovement that is the same in terms of timing, between homologous partsof the body. Incoherence or not being in phase refers to any feature ofmovement that differs in such terms between hemihalves of the body.

A body movement may be considered in terms of planes in which themovement occurs. Various planes relating to human anatomy have beendefined in the medical arts. These include a coronal plane (a planedividing the body into front and rear portions), a sagittal plane (aplane dividing the body into left and right portions), and a transverseplane (a plane dividing the body into upper and lower portions).

Generally speaking, epileptic movements typically are predominantlyuniplanar (i.e., they typically occur substantially mainly in one bodyplane) and in certain joints are bi-directional (e.g. elbowflexion/extension). Non-epileptic movements are often multiplanar and/ormultidirectional. FIGS. 28A-28B compare a non-limiting example of (a) agenerally planar epileptic movement and (b) a generally non-planarnon-epileptic movement of an arm 2810, as represented by the path tracedby an accelerometer 2820 (e.g., disposed on a lower arm of a patient, asseen from in front of, to the side of, and above the patient.

Body movements of the same joint(s) or muscle(s)/muscle group(s) on theright and left sides of the body may be considered “synchronized” or“synchronous” if their initiation and/or termination is substantiallysimultaneous. In general, epileptic movements involving more than onelimb or body part are more synchronous and symmetrical thannon-epileptic movements. Body movements of the same joint(s) ormuscle(s)/muscle group(s) on the right and left sides of the body may beconsidered “symmetrical” if they have substantially similar ranges ofmotion, velocities, amplitudes, directionalities, and/or planarities.

In a further embodiment, the neurologic activity not indicative of anepileptic seizure may further comprise at least one of: anelectroencephalographic (EEG) signal not indicative of an epilepticbrain activity of the patient, or a videographic motor activity analysisnot indicative of an epileptic motor activity of the patient. Suchfurther activities may assist in the classification performed at 2530.

In another particular example of body signals, the metabolic activitynot indicative of an epileptic seizure may be at least one of: a lack oflactic acidosis of the patient's blood sometime after the onset of ageneralized motor activity during the seizure, relative to a referencelactic acid value, or a lack of a normo-kalemic metabolic acidosis ofthe patient's blood sometime after the onset of a generalized motoractivity during the seizure, relative to a reference normo-kalemicvalue.

Any seizure may be subjected to the classification at 2530. For example,the method of this embodiment may allow the distinction of non-epilepticgeneralized seizures from epileptic generalized seizures. For anotherexample, the method of this embodiment may allow the distinction ofnon-epileptic partial seizures from epileptic partial seizures. Thepartial seizures may be simple partial or complex partial seizures.

If the seizure is to be classified as epileptic, this may be done at2550.

If the signals are not indicative of an epileptic seizure, then theseizure may be classified as non-epileptic at 2540. In one embodiment,no further actions need be taken.

In one optional embodiment, the method depicted in FIG. 25 furthercomprises at least one of: issuing at 2542 a notification that theseizure is non-epileptic, based upon classifying the seizure asnon-epileptic; cancelling at 2543 a notification or warning of anepileptic seizure, based upon classifying the seizure as non-epileptic;logging at 2544 at least one of the seizure classification (epileptic ornon-epileptic), the date of the seizure, the time of occurrence of theseizure, the severity of the seizure, the duration of the seizure, orthe time between seizures; preventing or warning at 2545 againstdelivery of a therapy for an epileptic seizure, based upon classifyingthe seizure as non-epileptic; administering at 2546 a therapy for thenon-epileptic seizure, based upon classifying the seizure isnon-epileptic; or discontinuing at 2547 delivery of a therapy for anepileptic seizures.

A notification that may be issued at 2542 may be issued to the patient,to a caregiver, or to medical personnel. In some embodiments, themedical personnel may be an emergency medical technician or an emergencyroom nurse or physician. The present inventor has firsthand knowledge ofa situation in which a patient presented at a rural emergency room inapparent status epilepticus, a life-threatening complication ofepilepsy. A helicopter ambulance service retrieved the patient andbrought him to the present inventor's current institution, a stateuniversity medical center having an advanced epilepsy care center. Uponthe patient's arrival, it was rapidly determined that the patient'sseizure was non-epileptic. Employment of the present method such thatthe rural emergency room personnel might have received a notificationissued at 2542 would have freed the helicopter ambulance service and theadvanced epilepsy care center for patients suffering from epilepticevents.

Regarding logging at 2544, the date and time of occurrence of theseizure need no further discussion. Severity may be defined using anyappropriate technique. In one embodiment, seizure severity may bedefined from one or more of the peak intensity of the seizure, theduration of the seizure, or the extent of spread of the seizure.Intensity, duration, and extent of spread may be measured usingneurologic, autonomic, metabolic, or other signals as described hereinand/or in patents and applications incorporated herein by reference.

Therapies that may be administered at 2546 may comprise cognitivetherapy, behavioral therapy, or biofeedback. For example, the patientmay receive a message that the seizure is non-epileptic, which may befollowed by instructions to relax, breathe deeply, or the like. Theresponse to one or more administered therapies may be measured (notshown) using body signals described above.

In another optional embodiment, a confirmatory notification of thenon-epileptic seizure may be issued at 2548. The issuance at 2548 may bebased on at least one of: an autonomic activity being an autonomicactivity not indicative of an epileptic seizure, a neurologic activitybeing a neurologic activity not indicative of an epileptic seizure, ametabolic activity being a metabolic activity not indicative of anepileptic seizure, an endocrine activity being an endocrine activity notindicative of an epileptic seizure, or a stress marker activity being astress marker activity not indicative of an epileptic seizure, whereinthe activity on which the issuing is based is different from theactivity on which the classifying is based.

Turning to FIG. 26 , a flowchart depiction of a method of distinguishingan epileptic seizure from a non-epileptic seizure is presented.

A first index and a second index, each selected from a neurologic index,an autonomic index, a metabolic index, an endocrine index, or a tissuestress marker index are analyzed at 2610. The indices may be any one ormore of the indices described above. In one embodiment, the analysis maycomprise determining whether the first index suggests the seizure isepileptic or non-epileptic; and determining whether the second indexsuggests the seizure is epileptic or non-epileptic.

Thereafter, a determination may be made at 2620 as to whether theanalysis at 2610 indicates (e.g., by matching signatures, features,values, or characteristics of indices belonging to the same class, or bycross-referencing signatures, features, values, or characteristics ofindices belonging to different classes) an epileptic event or anon-epileptic event. “Indicating” here does not refer a 100% match orperfect fit/correspondence to the signature, value or characteristic.Rather, as used herein, the match is to whichever of the epilepticsignature or features or the non-epileptic signature is closer to theanalysis made at 2610.

At least one further action may then be taken based on the analysis at2610. The at least one further action may be selected from: issuing at2632 a notification that the seizure is non-epileptic, based upon theanalysis of the first and second index indicating that the seizure isnon-epileptic; issuing at 2642 a notification or warning that theseizure is epileptic, based upon the analysis of the first and secondindex indicating that the seizure is epileptic; administering at 2634 atherapy appropriate for a non-epileptic seizure, based upon the analysisindicating that the seizure is non-epileptic; administering at 2644 atherapy for an epileptic seizure, based upon the analysis indicatingthat the seizure is an epileptic seizure; or logging at 2656 at leastone of the date of the seizure, the time of occurrence of the seizure,or the severity of the seizure, which may be desirable whether theseizure is epileptic or non-epileptic. FIG. 27 presents a flowchartdepiction of a method of distinguishing an epileptic seizure from anon-epileptic seizure. The method may comprise determining at 2710 afirst index selected from a neurologic index, an autonomic index, ametabolic index, an endocrine index, or a tissue stress marker indexbased on body data of a patient. In one embodiment, the first index isan autonomic index selected from a cardiac index, a respiratory index, atemperature index, an ocular index (e.g., pupillary size, rate changeand hippus), a chemical index (e.g., a concentration of a chemical in abody tissue), and a blood index. In one embodiment, the first index is aneurologic index selected from a kinetic index, a cognitive index, and aneurochemical index.

The first index may be compared to a reference value, as indicated at2715. Where the index crosses or exceeds the reference value, the firstindex may be used to trigger collection of additional body data and/orto determine additional body indices at 2720. For example, a cardiacindex (or an EEG, kinetic or endocrine index) may be used to triggerdetermination of either additional cardiac indices or of indicesbelonging to other classes (e.g., metabolic, neurologic, etc.). This mayinclude collection of, e.g., a second, third, fourth, etc. index for usein determining whether the seizure is epileptic or non-epileptic. Insome embodiment, each additional index may be triggered by some or allof the existing indices that have been determined.

The indices determined at 2710 and 2720 may be analyzed at 2725 todetermine one or both of an epileptic signature, 2730 or a non-epilepticsignature, 2740. The term “signature” is used herein to encompassvalues, characteristics, and other properties of the indices that areindicative of epileptic seizures or non-epileptic seizures.

The latency between the onset and termination of abnormal electricalactivity in the case of epileptic seizures and the first change from aninterictal baseline value varies among the different indices. Similarly,the time required for an index to return to its baseline value may varywidely. For example, the onset of abnormal/convulsive motor activity andloss of consciousness occurs nearly simultaneously with the onset ofabnormal generalized brain electrical activity, while oxygendesaturation may lag behind them by a few seconds and accumulation oflactic acid will not peak for a few minutes after the appearance ofabnormal kinetic/convulsive activity.

Recovery of these indices to interictal reference value does notparallel the temporal sequence of changes from inter-ictal to ictal:Oxygen saturation will recover shortly after the cessation of convulsiveactive while recovery of consciousness and cognitive functions andresolution of the lactic acidosis will take upwards of 30 min, in ahealthy subject. The application to this disclosure of microscopic,mesoscopic and macroscopic scales is appropriate and useful as theyencompass the multifarious times required for the various indices tochange from interictal to ictal and from ictal to post-ictal and finallyto interictal.

As previously noted, differences in the planarity of patient motions maybe useful in embodiments of the present disclosure to distinguishbetween epileptic and non-epileptic movements. In many cases,generalized epileptic movements are characterized by a high level ofplanarity. This is not to imply that epileptic movements are completelyplanar, but rather that such movements may be distinguished frommovements in non-epileptic seizures by comparing the movements in termsof their degree of uni-planarity, with epileptic seizures beingcharacterized by a significantly higher level of uni-planarity. In FIG.28(a), an accelerometer 2820 worn, for example, on a lower arm of apatient, may be used to determine a kinetic index or movement score thatindicates the movement is generally planar. As seen in the side and topviews, the arm movement occurs in a single plane. Although not fullyshown, the movement may also include flexion and/or bending at theelbow, while still remaining substantially planar.

In FIG. 28(b), in contract, as seen most clearly in the front and topviews, non-epileptic seizures are typically characterized by occurringin a random, multiplanar way. A kinetic index characterizing the levelof planarity of these movements would show a significantly differentvalue from the largely planar movements characteristic of seizures anddepicted in FIG. 28(a). In embodiments of the present disclosure,accelerometer calculations of the planarity of the movement—either aloneor in conjunction with other kinetic indices such as force, magnitude ofacceleration, etc.—may be used to characterize a seizure as eitherepileptic or non-epileptic.

In one embodiment, a method of distinguishing a non-epileptic seizurefrom an epileptic seizure in a patient may include: detecting a seizurein a patient based on at least one first body signal of the patientselected from an autonomic signal, a neurologic signal, a metabolicsignal, an endocrine signal, and a tissue stress marker signal;analyzing at least one second body signal of the patient selected froman autonomic signal, a neurologic signal, a metabolic signal, anendocrine signal, and a tissue stress marker signal; determining, basedon the analyzing of the at least one second body signal, at least afirst classification index comprising at least one of an epilepticseizure index and a non-epileptic seizure index; and/or classifying theseizure as one of a non-epileptic seizure or an epileptic seizure basedon the at least a first classification index.

In another example, classifying the seizure as one of a non-epilepticseizure or an epileptic seizure comprises classifying the seizure asnon-epileptic may be based on at least one of an epileptic seizure indexreaching or exceeding a threshold indicative of an epileptic seizure,and/or a non-epileptic seizure index reaching or exceeding a thresholdindicative of a non-epileptic seizure. Further, the at least one secondbody signal may include at least two body signals, each of said at leasttwo body signals being selected from an autonomic signal, a neurologicsignal, a metabolic signal, an endocrine signal, and a tissue stressmarker signal. In addition, the at least a first classification indexmay be at least one index selected from: an SaO2 index indicating thatthe patient's blood oxygen saturation is above a reference value afterthe onset of a generalized motor activity, a CO2 index indicating thatthe patient CO2 blood concentration is below a reference CO2 bloodconcentration after the onset of a generalized motor activity, a pHindex indicating that the pH of the patient's arterial blood is above areference value after the onset of a generalized motor activity relativeto a reference pH value, a pH index indicating the lack of a decrease ina pH value of said patient's arterial blood after the onset of ageneralized motor activity relative to a reference value, a bodytemperature index indicating that the patient's body temperature isbelow a reference value after the onset of a generalized motor activity,a cardiac index remaining below a reference value following onset ofgeneralized motor activity, an infrared index from a target portion ofthe patient's body remaining below a reference value after the onset ofa generalized motor activity; and/or a skin resistance index from atarget portion of the patient's body remaining outside the range ofvalue of a resistance index indicative of a generalized tonic, clonic,or tonic-clonic epileptic seizure. In addition, the at least a firstclassification index may be at least one kinetic index indicative of atleast one of: at least one of a repeating, periodic, or aperiodiccrescendo-decrescendo pattern of a motor activity of said patient, aforce of a motor activity that is outside epileptic seizure referencevalues; a range of motion of a motor activity of said patient that isoutside a range indicative of an epileptic seizure, a velocity of amotor activity of said patient that is outside a range indicative of anepileptic seizure, a multi-directionality of a motor activity of saidpatient that is outside a range of an epileptic seizure, amulti-planarity of a motor activity of said patient that is outside arange indicative of an epileptic seizure, a frequency of a motoractivity of said patient that is outside a frequency range of motoractivity of an epileptic seizure; a phase asynchrony between a first andsecond homologous body portions in a patient without pre-existing motordeficit; at least one of a difference in amplitude, force, velocity anddirection of movement between homologous first and second body portionsin a patient without pre-existing motor deficit having bilateralmovements; and/or a pelvic thrust or pelvic motor activity of saidpatient that is the most prominent body movement of said patient. Inaddition, the at least a first classification index may be aneurological index indicative of at least one of: a spontaneous orevoked cortical electrical signal not indicative of epileptic brainactivity of said patient; and/or a videographic image signal that is notindicative of an epileptic motor activity of said patient. In addition,the at least a first classification index may be at least one of ametabolic index selected from: a lactic acid concentration in thepatient's blood that remains below a reference concentration; a lacticacid concentration in the patient's blood indicative of a lack of lacticacidosis in said patient's blood after the onset of a generalized motoractivity, relative to an inter-ictal lactic acid value, and/or a normalserum potassium concentration in a patient with metabolic acidosis afterthe onset of a generalized motor activity. In addition, the method mayinclude: issuing a notification that the seizure is non-epileptic, basedupon classifying said seizure as non-epileptic; logging at least one ofthe date of the non-epileptic seizure, the time of occurrence of thenon-epileptic seizure, or the severity of the non-epileptic seizure;and/or administering a therapy for said non-epileptic seizure, basedupon classifying said seizure as non-epileptic. In addition, the methodmay include determining at least a second classification index selectedfrom: an autonomic index having a value or characteristic that is notindicative of an epileptic seizure, a neurologic index having a value orcharacteristic that is not indicative of an epileptic seizure, ametabolic index having a value or characteristic that is not indicativeof an epileptic seizure, an endocrine index having a value orcharacteristic that is not indicative of an epileptic seizure, and/or atissue stress marker index having a value or characteristic that is notindicative of an epileptic seizure, where classifying the seizure as anon-epileptic seizure is based at least in part upon both the firstclassification index and said second classification index. In addition,classifying the seizure as a non-epileptic seizure based on the at leasta first classification index may include classifying the seizure as anon-epileptic seizure only if the at least a first classification indexis within non-epileptic seizure reference values.

In another embodiment, a medical device system may include: at least onesensor configured to receive at least one of an autonomic signalindicative of an autonomic activity of a patient, a neurologic signalindicative of a neurologic activity of said patient, a metabolic signalindicative of a metabolic activity of said patient, an endocrine signalindicative of an endocrine activity of said patient, or a tissue stressmarker signal indicative of a tissue stress marker activity of saidpatient; a seizure detection unit configured to detect a seizure in apatient based on said at least one autonomic, neurologic, metabolic,endocrine, or tissue stress marker signal; at least one classificationindex determination unit configured to determine at least a firstclassification index selected from an autonomic index, a neurologicindex, a metabolic index, an endocrine index, and a tissue stress markerindex; and/or a seizure classification unit configured to classify saidepileptic seizure as one of an epileptic seizure and a non-epilepticseizure based at least in part on said at least a first classificationindex.

In addition, the classification index determination unit is configuredto determine at least one kinetic index indicating one of the onset or alack of generalized motor activity; and at least one autonomic indexselected from at least one of: an SaO2 index indicating that thepatient's blood oxygen saturation remains above a reference value aftersaid kinetic index indicates the onset of a generalized motor activity,a CO2 index indicating that the patient's CO2 blood concentrationremains below a reference CO2 blood concentration after said kineticindex indicates the onset of a generalized motor activity, a pH indexindicating that the pH of the patient's arterial blood remains above areference value after said kinetic index indicates the onset of ageneralized motor activity relative to a reference pH value, a pH indexindicating the lack of a decrease in a pH value of said patient'sarterial blood after said kinetic index indicates the onset of ageneralized motor activity relative to a reference value; a bodytemperature index indicating that the patient's body temperature remainsbelow a reference value after said kinetic index indicates the onset ofa generalized motor activity, a cardiac index indicating that cardiacindices are below a reference value after said kinetic index indicatesthe onset of generalized motor activity, and/or an infrared indexindicating that infrared radiation from a target portion of thepatient's body remains below a reference value after said kinetic indexindicates the onset of a generalized motor activity. In addition, afirst classification index is a neurological index comprising a kineticindex indicative of at least one of: a direction of movement of a targetportion of the patient's body in one plane, indicative of an epilepticseizure; a force of a motor activity of said patient that exceeds anepileptic seizure reference value, a range of motion of a motor activityof said patient that is within a range indicative of an epilepticseizure, a velocity of a movement of a target portion of the patient'sbody that is indicative of an epileptic seizure, a degree ofsynchronization or symmetry between movement of a right portion of thepatient's body and a left portion of the patient's body indicative of anepileptic seizure; a frequency of a movement of said patient that isindicative of an epileptic seizure; a joint position that is indicativeof an epileptic seizure; a body posture that is indicative of anepileptic seizure; a repeating, periodic or aperiodiccrescendo-decrescendo pattern of a motor activity of said patientcharacteristic of a non-epileptic seizure, a velocity of a motoractivity of said patient that is outside a range indicative of anepileptic seizure, a range of motion of a motor activity of said patientthat is indicative of a non-epileptic seizure, a velocity of a movementof a target portion of the patient's body that is indicative of anon-epileptic seizure; a force of a motor activity that is indicative ofa non-epileptic seizure; a multi-directionality of a motor activity ofsaid patient that is indicative of a non-epileptic seizure, amulti-planarity of a motor activity of said patient that is indicativeof a non-epileptic seizure, a frequency of a movement of a targetportion of the patient's body that is indicative of a non-epilepticseizure; a degree of synchronization or symmetry between movement of aright portion of the patient's body and a left portion of the patient'sbody indicative of a non-epileptic seizure; a joint position that isindicative of an epileptic seizure; a body posture that is indicative ofan epileptic seizure; and/or a pelvic thrust or pelvic motor activity ofsaid patient that is the most prominent body movement of said patientand is indicative of a non-epileptic seizure. In addition, the at leasta first classification index is at least one metabolic index selectedfrom: a lactic acid concentration in the patient's blood that remainsbelow a reference concentration; a lactic acid concentration in thepatient's blood indicative of a lack of lactic acidosis in saidpatient's blood after the onset of a generalized motor activity,relative to an inter-ictal lactic acid value, and a normal potassiumconcentration in a patient with metabolic acidosis after the onset of ageneralized motor activity. In addition, the medical device system mayinclude a therapy unit configured to provide at least one response tosaid classification unit classifying a detected seizure as anon-epileptic seizure, wherein said at least one response is selectedfrom administering a therapy appropriate for a non-epileptic seizure,discontinuing delivery of a therapy for epileptic seizures, preventingdelivery of a therapy for epileptic seizures, warning against deliveryof a therapy for epileptic seizure, cancelling a warning for anepileptic seizure; providing a notification that the seizure is anon-epileptic seizure; and/or logging the seizure as non-epileptic alongwith at least one of the date, time of occurrence, duration, orintensity of the non-epileptic seizure. In addition, the medical devicesystem may include a notification unit configured to notify at least oneof said patient, a caregiver, or a medical professional that saidseizure is non-epileptic, based upon said classification unitclassifying a detected seizure as a non-epileptic seizure.

In another embodiment, a method of distinguishing an epileptic seizurefrom a non-epileptic seizure may include: identifying an unclassifiedseizure; determining a first seizure classification index having anindex class selected from a neurologic index class, an autonomic indexclass, a motor index class, a tissue stress marker index class, or ametabolic index class; determining a second seizure classification indexhaving an index class selected from a neurologic index class, anautonomic index class, a motor index class, a tissue stress marker indexclass, or a metabolic index class; classifying said seizure as one of anepileptic seizure or a non-epileptic seizure based on both said firstand said second seizure classification indices; and/or taking at leastone further action based on said classifying, wherein said at least onefurther action is selected from: issuing a notification that the seizureis non-epileptic; issuing a notification that the seizure is epileptic;administering a therapy for a non-epileptic seizure; administering atherapy for an epileptic seizure; or logging at least one of whether theseizure is an epileptic or non-epileptic seizure and at least one of thedate of the seizure, the time of occurrence of the seizure, the severityof the seizure, the time elapsed from a previous seizure and thefrequency per unit time of the same type of seizure. In addition, theclassifying may include determining if said first and second seizureclassification indices match one of a signature of an epileptic seizure,a pattern of an epileptic seizure, a characteristic of an epilepticseizures, a signature of a non-epileptic seizure, a pattern of anon-epileptic seizure, and a characteristic of a non-epileptic seizure.

In another embodiment, a method may include: receiving a kinetic signalfrom at least one target of the patient's body; determining at least onekinetic index based on said kinetic signal; identifying an unclassifiedseizure based on the at least one kinetic index; receiving at least oneof a non-kinetic neurologic index and an autonomic index; and/orclassifying the seizure as an epileptic seizure or non-epileptic seizurebased on the at least one of a non-kinetic neurologic index and anautonomic index.

The above methods may be performed by a non-transitive computer readableprogram storage device encoded with instructions that, when executed bya computer, perform the method described herein.

All of the methods and apparatuses disclosed and claimed herein may bemade and executed without undue experimentation in light of the presentdisclosure. While the methods and apparatus of this disclosure have beendescribed in terms of particular embodiments, it will be apparent tothose skilled in the art that variations may be applied to the methodsand apparatus and in the steps, or in the sequence of steps, of themethod described herein without departing from the concept, spirit, andscope of the disclosure, as defined by the appended claims. It should beespecially apparent that the principles of the disclosure may be appliedto selected cranial nerves other than, or in addition to, the vagusnerve to achieve particular results in treating patients havingepilepsy, depression, or other medical conditions.

The particular embodiments disclosed above are illustrative only as thedisclosure may be modified and practiced in different but equivalentmanners apparent to those skilled in the art having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown other than as describedin the claims below. It is, therefore, evident that the particularembodiments disclosed above may be altered or modified and all suchvariations are considered within the scope and spirit of the disclosure.Accordingly, the protection sought herein is as set forth in the claimsbelow.

REFERENCES

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

-   U.S. patent application Ser. No. 12/756,065, filed Apr. 7, 2010-   U.S. patent application Ser. No. 12/770,562, filed Apr. 29, 2010-   U.S. patent application Ser. No. 12/896,525, filed Oct. 1, 2010-   U.S. patent application Ser. No. 13/040,996, filed Mar. 4, 2011-   U.S. patent application Ser. No. 13/091,033, filed Apr. 20, 2011-   U.S. patent application Ser. No. 13/098,262, filed Apr. 29, 2011-   U.S. Pat. No. 4,702,254-   U.S. Pat. No. 4,867,164-   U.S. Pat. No. 5,025,807-   U.S. Pat. No. 6,961,618-   U.S. Pat. No. 7,457,665

What is claimed:
 1. A method of treating a medical condition in apatient using an implantable medical device, the implantable medicaldevice including a first electrode coupled to a first cranial nervestructure and a second electrode coupled to a second cranial nervestructure, where the first cranial nerve structure is a left portion ofa cranial nerve and the second cranial nerve structure is a rightportion of the cranial nerve, the method comprising: detecting a seizurein a patient based on at least one first body signal of the patientselected from an autonomic signal, a neurologic signal, a metabolicsignal, an endocrine signal, and a tissue stress marker signal;providing a first electrical signal to the first cranial nerve structureof the patient; providing a second electrical signal to the secondcranial nerve structure; analyzing at least one second body signal ofthe patient selected from an autonomic signal, a neurologic signal, ametabolic signal, an endocrine signal, and a tissue stress markersignal; determining, based on the analyzing of the at least one secondbody signal, at least a first classification index comprising at leastone of an epileptic seizure index and a non-epileptic seizure index; andclassifying the seizure as one of a non-epileptic seizure or anepileptic seizure based on the at least the first classification index.2. The method of claim 1, wherein the first electric signal increases asympathetic tone to increase the heart rate of the patient.
 3. Themethod of claim 1, wherein the first electric signal decreases aparasympathetic tone to increase the heart rate of the patient.
 4. Themethod of claim 1, wherein the first electric signal decreases asympathetic tone to decrease the heart rate of the patient.
 5. Themethod of claim 1, wherein the first electric signal increases aparasympathetic tone to decrease the heart rate of the patient.
 6. Themethod of claim 1, wherein based on a determination that a seizure ischaracterized by a decrease in the heart rate of the patient, the firstelectric signal is applied to block action potential conduction on thevagus nerve.
 7. The method of claim 1, further comprising a heart unitand the method further comprising determining an inter-maxima intervaland an inter-minima interval between a first oscillation and a secondoscillation via the heart unit.
 8. The method of claim 7, furthercomprising a logic unit and the method further comprising comparing theinter-maxima interval and the inter-minima interval to an intervalthreshold via the logic unit.
 9. The method of claim 8, furthercomprises initiating one or more actions based on the interval thresholdbeing reached.
 10. A system for treating a medical condition in apatient, comprising: a sensor for sensing at least one body data stream;at least one electrode coupled to a vagus nerve of the patient; aprogrammable electrical signal generator; a heart rate unit capable ofdetermining a heart rate of the patient based on the at least one bodydata stream; and a logic unit configured via one or more processors tocompare a monitored value which is determined based on one or more datapoints relating to the heart rate to one or more threshold values, thelogic unit further configured to determine a first triggering eventbased on the comparison; wherein the one or more processors areconfigured to initiate one or more actions to change the heart rate ofthe patient based on the determination of the first triggering event.11. The system of claim 10, wherein the one or more processors areconfigured to increase a sympathetic tone or to decrease a sympathetictone to increase the heart rate of the patient based on the firsttriggering event.
 12. The system of claim 10, wherein the logic unit isfurther configured to determine a second triggering event based on thecomparison.
 13. The system of claim 12, wherein the one or moreprocessors are configured to decrease a sympathetic tone to decrease theheart rate of the patient based on the second triggering event.
 14. Thesystem of claim 10, wherein the logic unit is further configured todetermine a third triggering event based on the comparison.
 15. Thesystem of claim 14, wherein the one or more processors are configured todecrease the parasympathetic tone to increase the heart rate of thepatient based on the third triggering event.
 16. The system of claim 10,wherein the logic unit is further configured to determine an Nthtriggering event based on the comparison.
 17. The system of claim 16,wherein the one or more processors are configured to increase thesympathetic tone to increase the heart rate of the patient based on theNth triggering event.